Bufei Huoxue Capsule Attenuates PM2.5-Induced...
-
Upload
nguyenhanh -
Category
Documents
-
view
217 -
download
3
Transcript of Bufei Huoxue Capsule Attenuates PM2.5-Induced...
Research ArticleBufei Huoxue Capsule Attenuates PM25-InducedPulmonary Inflammation in Mice
Yue Jing12 Hongchun Zhang2 Zhe Cai3 Yukun Zhao4 YeWu56 Xuan Zheng5
Ying Liu7 Yuying Qin18 Mingjie Gu1 and Jin Jin1
1Graduate School Beijing University of Chinese Medicine 11 North 3rd Ring East Road Chaoyang DistrictBeijing 100029 China2National Clinical Research Center for Respiratory Diseases and Traditional Chinese Medicine Department of Pulmonary DiseasesChina-Japan Friendship Hospital 2 Yinghua Dongjie Hepingli Chaoyang District Beijing 100029 China3Clinical Research Institute China-Japan Friendship Hospital 2 Yinghua Dongjie Hepingli Chaoyang DistrictBeijing 100029 China4Institute of Basic Theory for Chinese Medicine China Academy of Chinese Medical Science 16 Dongzhimennei NanxiaojieDongcheng District Beijing 100700 China5School of Environment State Key Joint Laboratory of Environment Simulation and Pollution ControlTsinghua University Beijing 100084 China6State Environmental Protection Key Laboratory of Sources and Control of Air Pollution ComplexBeijing 100084 China7Geriatrics China-Japan Friendship Hospital 2 Yinghua Dongjie Hepingli Chaoyang District Beijing 100029 China8Zhengzhou Hospital of Traditional Chinese Medicine Zhengzhou City Henan Province 450008 China
Correspondence should be addressed to Hongchun Zhang hongchunzyahoocom
Received 21 October 2016 Revised 4 January 2017 Accepted 29 January 2017 Published 27 February 2017
Academic Editor Jae Youl Cho
Copyright copy 2017 Yue Jing et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Atmospheric fine particulate matter 25 (PM 25) may carry many toxic substances on its surface and this may pose a publichealth threat Epidemiological research indicates that cumulative ambient PM25 is correlated to morbidity and mortality due topulmonary and cardiovascular diseases and cancer Mitigating the toxic effects of PM25 is therefore highly desired Bufei Huoxue(BFHX) capsules have been used in China to treat pulmonary heart disease (cor pulmonale)Thus we assessed the effects of BFHXcapsules on PM25-induced pulmonary inflammation and the underlying mechanisms of action Using Polysearch and Cytoscape321 software pharmacological targets of BFHX capsules in atmospheric PM25-related respiratory disorders were predictedand found to be related to biological pathways of inflammation and immune function In a mouse model of PM25-inducedinflammation established with intranasal instillation of PM25 suspension BFHX significantly reduced pathological response andinflammatorymediators including IL-4 IL-6 IL-10 IL-8 TNF-120572 and IL-1120573 BFHX also reduced keratinocyte growth factor (KGF)secretory immunoglobulin A (sIgA) and collagen fibers deposition in lung and improved lung function Thus BFHX reducedpathological responses induced by PM25 possibly via regulation of inflammatory mediators in mouse lungs
1 Introduction
China has a substantial air pollution problem and of hazeepisodes correlate to atmospheric particulate matter abun-dance [1ndash3] Fine particulatematter with nominalmean aero-dynamic diameters of 25 120583m or less is defined as particulate
matter 25 (PM25) Although PM25 particles are small andbuoyant they carry many toxic substances on their surfaceand they can ldquohangrdquo in the atmosphere for some time andtravel great distances [4]Much epidemiological data indicatethat cumulative ambient fine particulate matter correlates tomorbidity of and mortality from pulmonary cardiovascular
HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017 Article ID 1575793 12 pageshttpsdoiorg10115520171575793
2 Evidence-Based Complementary and Alternative Medicine
diseases and cancer [5ndash12] and these problems represent asignificant social and economic burden
Based on systems biology and pharmacology networkpharmacology leverages network analysis and screens nodesto identify proteins critical to a disease for drug design[13 14] Network pharmacology can be used to investigatesynergism of multicomponent drugs to identify high efficacyand low toxicity agents with multiple targets [15 16] Chineseherbal formulas often have numerous targets and are com-prised of many substances so network pharmacologymay beuseful for studying traditional Chinese medicine [17 18]
Bufei Huoxue (BFHX) capsules contain three commonChinese herbal products Astragalus radix paeoniae rubraand Psoralea corylifolia and have been approved by the ChinaFood and Drug Administration (Number Z20030063) forthe treatment of pulmonary heart disease Clinical studiessuggest that these compounds improve pulmonary ventila-tion function and reduce silicosis and lung inflammation[19ndash21] Thus we studied BFHX capsules and PM25-relatedrespiratory disease using a network pharmacology platformThe effects of BFHX capsules on PM25-induced pulmonaryinflammation were evaluated and the underlying mecha-nisms of action were investigated in mice
2 Materials and Methods
21 PM25-Related Diseases PM25-related diseases wereidentified using Polysearch System (httpwishartbiologyualbertacapolysearchindexhtm) a web-based text-min-ing system for extracting relationships among human dis-eases genes drugs and metabolism PM25-related dis-eases were searched and extracted statements were manuallyscreened According to 119885-values the top 10 diseases wereselected for further study
22 Prediction of Disease Pathways and BFHX Targets Alltarget genes or proteins for each BFHX component (Astra-galus radix paeoniae rubra and Psoralea corylifolia) wereobtained using Polysearch and diseases were selected frompredictions based on keywords Targets were networked andvisualized using Cytoscape 321 software Drug- and disease-related targets were merged using Merge to screen key targetproteins
23 PM25 Mouse Model and Drug Intervention
231 PM25 Sampling and Suspension Preparation PM25samples were collected from three sites in Beijing in thesummer and winter seasons of 2011 and 2012 The three siteswere a roadside site located 2m from the curb of the North4th Ring Road an urban site on the campus of Tsinghua Uni-versity and a rural site situated in the countryside of MiyunSampling was conducted by Anderson particulate samplerHBL-GUV (Thermo Fisher Waltham MA) equipped witha PTFE membrane for two consecutive weeks [22] At theend of sample collection the PTFE membrane carryingPM25 was cut into 1 times 3 cm pieces and placed in ultrapurewater Particles were eluted three times under ultrasonic
oscillation 40min each Liquid containing the particulatematter was filtered through six layers of sterile gauze andcentrifuged at 12000 rpm at 4∘C for 30min The lower layerof the suspension was collected and vacuum-freeze dried toyield PM25 particles which were then stored at minus20∘C Tomake a stock solution PM25 particles were weighed andsuspended in saline at the desired concentrations after beingultrasonicated for 15min and sterilized Samples were storedat 4∘C Detailedmethods can be found in related papers by usand other authors [23 24]
232 Drugs BFHX capsules were provided by Lei Yun ShangPharmaceutical Limited (Suzhou Jiangsu China) The drypowder was taken from the capsules and suspended indistilled water The mixture was stored at 4∘C
233 Animals Adult female ICR mice (Beijing HFKBiotechnology Co Ltd China 22ndash26 g) were housed inseparate cages with food and water freely available understandard laboratory conditions of 22ndash28∘C and relativehumidity of 50ndash60 with a 12 h light12 h dark cycle Animaltreatment and maintenance were performed in accordancewith requirements of and the study protocol was approvedby the institutional animal care and use committee at theChina-Japan Friendship Hospital in Beijing (Permit 150202) All efforts were made to minimize suffering
Sixty ICR female mice were randomized into 3 groupsnormal controls PM25 exposure and BFHX interventiongroups (119873 = 20group) Controls were given an intranasalinstillation of saline (20120583lmouse) on days 1 8 15 and 22ThePM25 exposure group was given an intranasal instillation ofPM25 suspension (40mgkg 20 120583lmouse) on days 1 8 15and 22 and each received oral saline (02mlmouseday) fromdays 1 to 22 The BFHX intervention group was treated aswas the PM25 exposure group except that BFHX (082 gkg02mlmouseday) instead of saline was given daily Animalswere sacrificed 48 h after the last treatment
24 Lung Function Mice were anesthetized with 2 pento-barbital (04ml40 g ip) and secured in a supine position tobe orotracheally intubated Then mice were transferred toa plethysmography platform and lung function analysis wasmeasured lung include inspiratory resistance (RL) expira-tory resistance (RE) dynamic lung compliance (Cdyn) andpeak expiratory flow (PEF) using an AniRes2005 apparatus(Beilanbo Science and Technology Co Ltd Beijing China)
25 Lung Histology Mice were sacrificed and subjected tothoracotomy with lung resectionThe left lung lobe was fixedin 10 formalin for 24 h and then dehydrated embeddedin paraffin and sectioned Sections were stained with hema-toxylin and eosin (HampE) according to the routine stainingmethod and observed under an optical microscopeThe rightlung lobe was homogenized for molecular studies
26 Masson Staining Lung collagen content was quantifiedwith Masson trichrome staining Paraffin sections were firstdewaxed followed by washing with tap and then distilled
Evidence-Based Complementary and Alternative Medicine 3
water Sections were then stained to identify nuclei withRegaud or Weigert hematoxylin for 5ndash10min After fullywashing with water slides were washed with distilled waterand treated with Ponceau Masson Acid fuchsin solutionfor 5ndash10min Sections were then briefly immersed in a 2aqueous acetic acid solution and then treated with 1 phos-phomolybdic acid for 3ndash5min followed by direct stainingwith aniline blue or light green liquid dye for 5min Aftera brief Immersion in 02 acetic acid sections were treatedwith 95 alcohol ethanol and transparent xylene and thencemented with neutral gum For each slice six fields (under200x magnification) were selected Positive Masson stainingfor collagen depositionwas analyzed using by Image-Pro Plusmultimedia color pathological image analysis software Theratio of collagen deposition to the viewed area was calculatedand averaged
27 KGFandHMGB1Expression in LungTissue Keratinocytegrowth factor (KGF) antibody was purchased from Biorbyt(Cambridge UK) and the immunohistochemistry kit wasfrom Gene Technology (Shanghai China) High mobilitygroup box 1 protein (HMGB1) antibody was purchasedfrom Santa Cruz Biotechnology (Santa Cruz CA) andthe immunohistochemistry kit was from Gene Technology(Shanghai China) Lung tissue sections were deparaffinizedaccording to kit instructions and then stained with hema-toxylin and viewed with light microscopy Images wereanalyzed with Media Cybernetics Image-Pro Plus imageanalysis software Each slice was assessed using 6 fields ofintegrated optical density (IOD) which represented proteinexpression
28 Measurement of Inflammatory Mediators and sIgA byELISA The sacrificed mice were placed in a supine positionand perfused with two 075ml aliquots of ice-cold normalsaline (NS) Each animal was lavaged five times Lavage fluidwas collected and the cellular contents and bronchoalveolarlavage (BAL) fluid were separated by centrifugation Super-natant was used to measure secretory immunoglobulin A(sIgA) with enzyme-linked immunosorbent assay (ELISA)kits (Abbexa Cambridge UK) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)
Lung tissue (01 g) was placed in a 15ml EP tube toprepare 10 lung homogenate Homogenate was centrifugedat 12000 rpm and 4∘C for 20min Supernatant used tomeasure inflammatory mediators from interleukin-4 (IL-4) interleukin-6 (IL-6) interleukin-10 (IL-10) interleukin-17 (IL-17) interleukin-1120573 (IL-1120573) and tumor necrosis factor(TNF-120572) with enzyme-linked immunosorbent assay (ELISA)kits (R amp D Minneapolis MN) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)
29 Real-Time Reverse Transcriptase Polymerase Chain Reac-tion (RT-PCR) RT-PCR was used to measure IL-8 and IgAexpression in mouse lung tissues Total RNA was extractedfrom 100mg lung tissuewithTrizol after a one-step extraction
Table 1 PM25-related diseases identified through Polysearch
Number 119885 score Disease name1 9 Respiratory disease2 81 Asthma3 77 Lung cancer4 58 Cardiovascular disease5 37 COPD6 22 Atherosclerosis7 12 Ischemic stroke8 08 Pneumonia9 07 Gestational diabetes mellitus10 07 Pulmonary embolism
protocol cDNA was synthesized by reverse transcriptionwith 2120583g RNA 1 120583l oligo (dT) and DEPC water and 12 120583llung tissue 120573-Actin primer sequence is as follows forwardprimer 51015840-GTGACGTTGACATCCGTAAAGA-31015840 and thereverse primer 51015840-GTAACAGTCCGCCTAGAAGCAC-31015840IL-8 primer sequence is as follows forward primer 51015840-CATCTTCGTCCGTCCCTGTG-31015840 and reverse primer 51015840-GCCAACAGTAGCCTTCACCCA-31015840 IgA primer sequenceis as follows forward primer 51015840-GCTACAGTGTGTCCA-GCGTCCT-31015840 and reverse primer 51015840-TGCCAGACTCAG-GATGGGTAAC-31015840 Quantitative analysis was performedusing the 2minusΔΔCt method
3 Statistics
Data are represented as means plusmn standard deviation Sta-tistical analysis was conducted with SPSS 170 softwareComparisons among multiple groups were analyzed withone-way ANOVA with a Tukey-Kramer post hoc correctionSingle comparisons were made with an unpaired two-tailedStudentrsquos 119905-test Differences were considered statistically sig-nificant if 119901 lt 005
4 Results
41 PM25-Related Disease Prioritization and Predicted Tar-gets Polysearch platform analysis yielded a list of PM25related diseases (Table 1) which were prioritized based ona relevancy score and expressed as a 119885 score which refersto the number of standard deviations of the relevancy scoreabove the mean value A higher 119885 score denotes a lesserlikelihood that the outcome is due to chance Polysearchplatform queries confirmed that 98 10 and 9 target proteinswere associated with Astragalus radix paeoniae rubra andPsoralea corylifolia respectively (Figures 1ndash5)
42 Effect of BFHX on Mouse Pulmonary Function Com-pared with controls lung inspiratory and expiratory resis-tances were significantly greater (119901 lt 001 119901 lt 005)in PM25 mice Airway compliance and maximum forcedexpiratory flow were less in PM25 mice BFHX intervention
4 Evidence-Based Complementary and Alternative Medicine
HMOXLTB4DH CA1 BALp38
TelomeraseSuccinate
dehydrogenase(protein family
or complex) TGFB1 VEGF
TIMP1
ornithinedecarboxylase
ioredoxin
PHT1
albumin
5lipoxygenase
acetylcholinereceptor
AMPK
AS160Radixpaeoniaerubra
MAPK
Bcl2
T bet
Superoxidedismutase
Notch1NFATc3
ATPase PI3KAT2
p65
complementC3
ATF6
P glycoprotein
BFGF
PARP
IL10
CXCL12
CATCYP3A4
EC-NOSCyclin
dependentkinases
(protein family or complex)
G-CSF
Heparanase
TG2
Gracile
VCAM1 keap1
aFGFALDR
TyrosinaseTNFR1
A10
Sirtuin 1TRPA1
TSLPIL17 IL13ABPA
B7H3AdiponectinIgE
BDNFPeriostinBeta CateninVisfatin
Psoraleacorylifolia
Monoamineoxidases
CES1
Smoothmuscle actin
complex I CASP3 CYC
ERA
PTP1BCalcineurin
(protein family or complex)
CD35PPARA CCL2
Protein kinase D1
CD45
PSAP CCR5CD11c
SERCA2 AGT JNK3CD8 CCL5IL8
SAPS
LDHMMP1IL2
Pyrophosphatase
PPARG Myostatin IFNgammaAstragalus
c Jun N terminalkinase
PendrinICAM1SulfatetransportersCaspase 3
N33IL4
MLCK
MicroRNA
IL6
LAMA
TNFA IVF
CD4
CD25
Statins Myosin
STAT1
STAT3
MMP2MMP9
MTL4MUC1
NPYIL1B
Calpain(protein family
or complex)
IL18
IL12
TLR4CAPE
IL15
MTHFR
CD69
ImmunoglobulinIL5
Interleukins
IL33 IL17F CC16ADAM33
HMGB1HASC
GATA3
GAP43
PBE
ORMDL3
CTLA4
Chitinase
5lipoxygenaseCD86
EGFR
Asthma
Interleukin 5
MicroRNAsChymase
proteinTyrosine
phosphatase
Figure 1 Potential targets of BFHX in asthma Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents asthma round blue nodes represent drug targets red nodes represent drug targets of disease
P53 MTHFR MicroRNAs
EML4EGFR
E cadherin
Lung cancer
CYP4502A6
p21 protein
Fascin
B7H1
PTEN
HER2
Beta catenin
KRAS
LUNX
MALAT1
MDM2 c Myc
GSTT1
CHRNA5
CHRNA3
GSTP1
CEACAM5
CDK2
HSP90AB1
CD133CXCR4
CYP1B1
CYP2E1
FBP1
GSTM1
IL10
Bcl2
MAPK
MMP9
STAT3
MMP2
TERT
STK11
SCLC
ROS1
RASSF1A
TRAF6
HMOX
Radixpaeoniaerubra
BALLTB4DH
CD35
Calpain(protein family
or complex)
P glycoprotein
CD8
Chymase
CCR5
CD69
Cyclindependentkinases
(protein family or complex)
c Jun N terminalkinase
AS160
Albumin
AMPK
ALDR
CD11c
IL18
Heparanase
Gracile
IL1B
G-CSF
MUC1
CD25
MTL4
CYP3A4
N33
JNK3
Astragalus
ICAM1
IL8
Myosin
Myostatin
keap1Interleukin 5
LDH
NFATc3
IL12
TIMP1
TelomeraseTG2
TGFB1
ioredoxin
IFNgamma
Notch1Ornithine
decarboxylase
IL15
PPARA
Superoxidedismutase
Proteintyrosine
phosphatase
PHT1
MicroRNAs
MMP1
ATF6ATPase
EC-NOS
IL2
BFGFPTP1B
Protein kinase D1
Succinatedehydrogenase(protein family
or complex)
Calcineurin(protein family
or complex)
PSAP
SAPS
Pyrophosphatase
SERCA2
IL6
CA1
CASP3
CXCL12
PI3K
CAPETyrosinase
PPARGp65CD4 Statins
STAT1Caspase 3
CD45 CATSulfatetransporters
VCAM1TNFR1
TNFATLR4
T betVEGF
ComplementC3
AGTAT2
CCL5A10
Acetylcholinereceptor
CCL2
5lipoxygenase
aFGF
complex I
Smoothmuscle actin
Psoraleacorylifolia
Monoamineoxidases CYCPARP ERACES1
p38 IL4
WISP1XRCC1
XRCC3ABCB1ALDH1ALK
API4
CLPTM1LVEGFR2 BRAFmiR21IL17
CK19VIMPIK3CA
BCRP
Figure 2 Potential targets of BFHX in lung cancer Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents lung cancer round blue nodes represent drug targets red nodes represent drug targets of disease
significantly decreased inspiratory (119901 lt 001) and expiratoryresistance (119901 lt 005) and increased dynamic lung complianceand maximum forced expiratory flow (119901 lt 001) in PM25mice Thus BFHX intervention significantly improved lungfunction and reduced airway resistance and increased airwaycompliance (Figure 6) in PM25 mice
43 Effect of BFHX on PM25-Induced Pulmonary Histopa-thology in Mice In the normal group and the BFHX groupbronchial mucosa and bronchial wall structures were intactand alveolar structural integrity was intact Some inflam-matory cells had infiltrated alveolar spaces but there waslittle interstitial inflammation and lung capillary structures
were intact with no bleeding Figure 7 shows that com-pared with the normal group and the BFHX group PM25exposure caused histological injury such as widened alveolarsepta capillary congestion and minor hemorrhages of smallairways BFHX treatment significantly reduced histologicalinjury and reduced congestion and hemorrhage of smallairways and recruitment
44 Effect of BFHX on Lung Collagen Deposition in MiceControls had collagen deposition in many small airways andfibrosis was noted around the vascular wall PM25-exposedlung tissues had thickened airways with obvious collagendeposition smaller alveoli with wider septa and obvious
Evidence-Based Complementary and Alternative Medicine 5
NFE2L2
Interleukin
S100B
SERPINA1
SERPINE2
SFTP1
Paraoxonase
MMP20mtTFA
Neutrophilelastase
Acetylcholinereceptors HTR4
GATA3
IL13
MicroRNAsMMP12
LAMALeptin
GSTP1
GSTM1
CHRNA5
CHRNA3
Chemokines
CFTR
HMGB1OPG
Hemoglobin
GSTT1ElastinFOXP3
IL17
HHIP
HD2
IREB2
COPD
EGR1
CXCR2
CYP1A1
EGLN2
EGFR
Immunoglobulin
PDE4A
IL33
IL32
IL22
MMP9
TIMP1
MAPK
p38
IL8
IL1B
IL6
IL10
VEGF
PI3K
Ornithinedecarboxylase
IFNgamma
Tyrosinase
MMP2
Acetylcholinereceptor
AMPK
EC-NOS
CYP3A4
AT2MUC1Myosin
MyostatinN33
Calpain(protein family
or complex) chymase
c Jun N terminalKinase
ATPase
Calcineurin(protein family
or complex)
CD35
CD25
CD45BFGF
CD69
complementC3
AstragalusVCAM1
Succinatedehydrogenase(protein family
or complex)
CD11cATF6
G-CSF
IL18Heparanase
ICAM1IL12IL15IL2
Gracile
P glycoprotein
Notch1
Superoxidedismutase
NFATc3
PHT1
PTP1B
Pyrophosphatase
PSAP
protein kinase D1
5lipoxygenase
JNK3
PPARG
PPARA
Interleukin 5
SAPS
LDH
MicroRNAs
PTX3
SOCS3
TRAIL
ROR1SPD
RAGE
Surfactantprotein B
Sirtuin1
CD11b
CCSP
CTRP5
CTLA4
Cyclindependent
kinases(protein family
or complex) AS160
CCR5CCL5
CCL2CATCaspase 3
CA1CXCL12
BAL
IL4LTB4DH Bcl2
Sulfatetransporters
MTL4 keap1
STAT3
CAPE
Proteintyrosine
phosphatase
A10
p65
TGFB1ioredoxin
STAT1
TNFR1TLR4
ALDR
aFGFAGT
Albumin
MMP1
Smoothmuscle actin
PARP
CASP3ERA
CYC
Monoamineoxidases
complex I
CES1HMOX
CD8
TelomeraseCD4
SERCA2TNFA
T bet
TG2Statins
ADAM33IgEACHE
XRCC5
S100A4
Ubiquitin
CPAP
VDB
COX2
Adiponectin
BD1CRP
AQP5
CST3
BAFF
ADRB2 Radixpaeoniae
rubraPsoraleacorylifolia
Figure 3 Potential targets of BFHX in COPD Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents COPD round blue nodes represent drug targets red nodes represent drug targets of disease
GAP
AD7
gp91phox
ADAM33
GBP5
ADPRTADAM28
ADAM10
Gal3Phe3
TREM1
PAG1
UPA
PFGE
ACHEVWF
Ferritin
AD3
PIGN
ASCABPA
Fatty acid bindingprotein Transferrin
ZFP36L1
C10CA125
Chitinase 3 like 1 COPD6 Pneumonia
CPAP
BDNFHAP
HCAP Bradykinin
HELIOS AvianB99ARG1
FER
CD86
ChitinaseCFTR
CVID
CSF2CTLA3CTRL CMH7COLEC7CRP
CTSS
IMP 1ImportinIPS
ImmunoglobulinKidsK20
IRF5Interleukins
O13
NOD2NTMProgranulin Interferon
PPTOSM
IL25
PRSPPAI1
PLEKHA7 p42P2Y2Prothrombin
BALLTB4DHCA1
IL1B
HMOXCXCL12
TNFA
Acetylcholinereceptor
IL12
VEGF
IL8
CD4
STAT3
Statins
TGFB1
Telomerase
PPARG
Succinatedehydrogenase
(proteinfamily or complex)
T bet Proteinkinase D1
ioredoxin
p38
TIMP1
PTP1BTG2
SERCA2
SAPS
Superoxidedismutase
Sulfatetransporters
Cyclindependent
kinases(proteinfamily or complex)
STAT1
Pyrophosphatase
NFATc3
PHT1
CD69p65
Ornithinedecarboxylase
Chymase
PGlycoprotein
Notch1N33
LDH
TNFR1
IL18Interleukin 5
CD8
PSAP
CYP3A4
PI3K
PPARA
Myosin
EC-NOS
IL4
IL10AGT
IL6
TLR4
PSA
PTX3PSPC
REL
Q10RAGE
PSPB
SCT
SPIN
SCAP
SFTPA2
SOD
SCCA
SIGIRR
SARS
SAPS2
SCIN
Lipocalin 2
MAPK
MAC387
LEPR
MBL
MDP
ST2TFI
MLKL
Endoglin
Tie2
MincleETT
MRP8P97
MPO
rombomodulin
TPATR
TLR9
TLR1TLR2
TRAF6
DHPS
CXCL5
DHRS2
CXCL2
ELA2
CytolysinCYLD
EGFR
DHFR
RIP1
LAMP
LAMA
CXCL1
L12L selectin
RF
SAARIP3
Smoothmuscle
actinCYCComplex I
CASP3PARP
ERAMonoamineoxidases
CES1
ATF6c Jun N
terminalkinase
ComplementC3
AS160AT2
Calcineurin(proteinfamily or complex)BFGF
proteinTyrosine
phosphatase
Myostatin
MMP1CD45MMP2
MMP9
CD35
MTL4MUC1
ICAM1Caspase 3CAPE
Astragalus
ATPase
IFNgamma
TyrosinaseHeparanase
CAT
G-CSF
Gracile
CD11cCCR5
JNK3
CCL2
IL2CCL5
IL15
aFGF
VCAM1
ALDRAlbumin
Bcl2 MAPK
AMPK
5Lipoxygenase
A10
Keap1MicroRNAsCalpain
(proteinfamily or complex)
CD25
HFABP
Heparanase AnnexinsHemopexin Annexin A1
ANX2
CD44CD143
CBG
CABP
CD62
CCCKR4
CalciumChannel
CD64
AFP
AminopeptidaseALB
AHF
ANGPTL2Hemoglobin
HIES
Hla a
HGF
IFNG
ICS
HMGB1
HSPC008
IgE
Musashi1
IL22
ICOS
Neuraminidase
Plasminogen
IL16
Muscles
IL17IL1RA
IL13
HP
APA
HSP72
BNP32
HSP60
ATP12A
AQP4
APOB100
HLAHLADOA
Atg16L1
PsoraleacorylifoliaRadix
paeoniaerubra
DRB1lowast11
Figure 4 Potential targets of BFHX in pneumonia Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents pneumonia round blue nodes represent drug targets red nodes represent drug targets of disease
fibrosis Compared with PM25 lungs BFHX-treated tissuehad less tracheal and lung interstitial fibrosis (Figure 8)ThusBFHX significantly alleviated collagen deposition in PM25mice
45 Effect of BFHX on HMGB1 and KGF Expression inMouse Lung Tissues HMGB1 expression in alveolar tissue
was significantly greater in PM25 tissues compared withcontrols (119901 lt 001) and the BFHX intervention group (119901 lt001 Figures 9(a) and 9(c)) suggesting reduced inflammationwas due to BFHX Also in lung tissue of PM25-exposedanimals KGF expression in tracheal mucosa and alveolartissue was significantly greater than in normal mice and theBFHX intervention group (119901 lt 005 Figures 9(b) and 9(d))
6 Evidence-Based Complementary and Alternative Medicine
HFABP
HMOX1Integrin
HaptoglobinHemoglobin
IFB BAL
IL10 p38
LTB4DH CA1HMOX
MAPK
CXCL12
IL4Bcl2
Pulmonary
embolism
cTnI
ASPS
CXCL4FGFR2
CRAT
CD309
ERA
PARPCYC
Complex I
CASP3
Monoamine
Smoothmuscle actin
CES1
VEGF
Albumin
Statins
IL6
CYP3A4
PSAP
BET1
ADM
APE
ANPB
ACPAArginase
FX
APC
CTPA
cTnT
Interferon
CRP
ARF
APS
ARG2
APOE
GPVI
CYP2C9
FDG
GGT
ADAMTS13
TIMP1
Proteintyrosine
phosphatase
Superoxidedismutase
Succinatedehydrogenase(protein family
or complex)
ioredoxin
TG2
BMPR2BNP
CD62
CD62E
PLJAMA
PAI1
Interleukins
Factor VIIa
MicroRNA134MMP20
MTHFR
SERPINC1
PVAPROS
SMARCAL1
Plasminogen
SCUBE1
PROC
NOS3
NPSA
PERC
Methemoglobin
Immunoglobulin
TPA
SERPINA1
SPARrombin
romboplastin
VKORC1
VV
PASP
Muscles
PATE
JAK2
KS1
TNFA
5lipoxygenase
PPARG
TNFR1Tyrosinase
PPARA
VCAM1
aFGF
Caspase 3MMP9
ATPase
IL8
Heparanase
Interleukin 5BFGF
Astragalus
IL2
PTP1B
ICAM1STAT1
SERCA2
MMP2PI3K
MMP1
G-CSF SAPS
Gracile
c Jun N terminalkinase
Calcineurin(protein family
or complex)
AS160
AGT
Calpain(protein family
or complex) ALDR
Acetylcholinereceptor
AMPK
A10
STAT3IL1B
ATF6
keap1T bet
ComplementC3
IL12
IL18CD45 AT2IL15
TelomeraseCCR5
MicroRNAs
CCL5
LDH
Ornithinedecarboxylase
NFATc3
CD11c
Notch1
CD35
P glycoprotein
Myostatin
CD4
N33 CCL2
MUC1
Cyclindependent
kinases(protein family
or complex) JNK3MTL4
CATMyosin
CAPE
Sulfatetransporters
CD69
Chymase
CD8
PHT1
IFNgamma
EC-NOS
p65
CD25
Protein kinase D1
TLR4
TGFB1Pyrophosphatase
Radixpaeoniae
rubra
oxidases
Psoraleacorylifolia
Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease
Normal Model BFHX00
05
10
15
RL-m
ean
(cm
H2Omiddots
m)
lowastlowast lowastlowast
(a)Normal Model BFHX
00
05
10
15
20
25
lowast lowast
RL-m
ean
(cm
H2Omiddots
m)
(b)
Normal Model BFHX000
002
004
006
Cdy
n-m
ean
(mlc
mH
2O
)
lowastlowast
lowastlowast
(c)Normal Model BFHX
0
1
2
3
PEF
(mls
)
lowast lowastlowast
(d)
Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
2 Evidence-Based Complementary and Alternative Medicine
diseases and cancer [5ndash12] and these problems represent asignificant social and economic burden
Based on systems biology and pharmacology networkpharmacology leverages network analysis and screens nodesto identify proteins critical to a disease for drug design[13 14] Network pharmacology can be used to investigatesynergism of multicomponent drugs to identify high efficacyand low toxicity agents with multiple targets [15 16] Chineseherbal formulas often have numerous targets and are com-prised of many substances so network pharmacologymay beuseful for studying traditional Chinese medicine [17 18]
Bufei Huoxue (BFHX) capsules contain three commonChinese herbal products Astragalus radix paeoniae rubraand Psoralea corylifolia and have been approved by the ChinaFood and Drug Administration (Number Z20030063) forthe treatment of pulmonary heart disease Clinical studiessuggest that these compounds improve pulmonary ventila-tion function and reduce silicosis and lung inflammation[19ndash21] Thus we studied BFHX capsules and PM25-relatedrespiratory disease using a network pharmacology platformThe effects of BFHX capsules on PM25-induced pulmonaryinflammation were evaluated and the underlying mecha-nisms of action were investigated in mice
2 Materials and Methods
21 PM25-Related Diseases PM25-related diseases wereidentified using Polysearch System (httpwishartbiologyualbertacapolysearchindexhtm) a web-based text-min-ing system for extracting relationships among human dis-eases genes drugs and metabolism PM25-related dis-eases were searched and extracted statements were manuallyscreened According to 119885-values the top 10 diseases wereselected for further study
22 Prediction of Disease Pathways and BFHX Targets Alltarget genes or proteins for each BFHX component (Astra-galus radix paeoniae rubra and Psoralea corylifolia) wereobtained using Polysearch and diseases were selected frompredictions based on keywords Targets were networked andvisualized using Cytoscape 321 software Drug- and disease-related targets were merged using Merge to screen key targetproteins
23 PM25 Mouse Model and Drug Intervention
231 PM25 Sampling and Suspension Preparation PM25samples were collected from three sites in Beijing in thesummer and winter seasons of 2011 and 2012 The three siteswere a roadside site located 2m from the curb of the North4th Ring Road an urban site on the campus of Tsinghua Uni-versity and a rural site situated in the countryside of MiyunSampling was conducted by Anderson particulate samplerHBL-GUV (Thermo Fisher Waltham MA) equipped witha PTFE membrane for two consecutive weeks [22] At theend of sample collection the PTFE membrane carryingPM25 was cut into 1 times 3 cm pieces and placed in ultrapurewater Particles were eluted three times under ultrasonic
oscillation 40min each Liquid containing the particulatematter was filtered through six layers of sterile gauze andcentrifuged at 12000 rpm at 4∘C for 30min The lower layerof the suspension was collected and vacuum-freeze dried toyield PM25 particles which were then stored at minus20∘C Tomake a stock solution PM25 particles were weighed andsuspended in saline at the desired concentrations after beingultrasonicated for 15min and sterilized Samples were storedat 4∘C Detailedmethods can be found in related papers by usand other authors [23 24]
232 Drugs BFHX capsules were provided by Lei Yun ShangPharmaceutical Limited (Suzhou Jiangsu China) The drypowder was taken from the capsules and suspended indistilled water The mixture was stored at 4∘C
233 Animals Adult female ICR mice (Beijing HFKBiotechnology Co Ltd China 22ndash26 g) were housed inseparate cages with food and water freely available understandard laboratory conditions of 22ndash28∘C and relativehumidity of 50ndash60 with a 12 h light12 h dark cycle Animaltreatment and maintenance were performed in accordancewith requirements of and the study protocol was approvedby the institutional animal care and use committee at theChina-Japan Friendship Hospital in Beijing (Permit 150202) All efforts were made to minimize suffering
Sixty ICR female mice were randomized into 3 groupsnormal controls PM25 exposure and BFHX interventiongroups (119873 = 20group) Controls were given an intranasalinstillation of saline (20120583lmouse) on days 1 8 15 and 22ThePM25 exposure group was given an intranasal instillation ofPM25 suspension (40mgkg 20 120583lmouse) on days 1 8 15and 22 and each received oral saline (02mlmouseday) fromdays 1 to 22 The BFHX intervention group was treated aswas the PM25 exposure group except that BFHX (082 gkg02mlmouseday) instead of saline was given daily Animalswere sacrificed 48 h after the last treatment
24 Lung Function Mice were anesthetized with 2 pento-barbital (04ml40 g ip) and secured in a supine position tobe orotracheally intubated Then mice were transferred toa plethysmography platform and lung function analysis wasmeasured lung include inspiratory resistance (RL) expira-tory resistance (RE) dynamic lung compliance (Cdyn) andpeak expiratory flow (PEF) using an AniRes2005 apparatus(Beilanbo Science and Technology Co Ltd Beijing China)
25 Lung Histology Mice were sacrificed and subjected tothoracotomy with lung resectionThe left lung lobe was fixedin 10 formalin for 24 h and then dehydrated embeddedin paraffin and sectioned Sections were stained with hema-toxylin and eosin (HampE) according to the routine stainingmethod and observed under an optical microscopeThe rightlung lobe was homogenized for molecular studies
26 Masson Staining Lung collagen content was quantifiedwith Masson trichrome staining Paraffin sections were firstdewaxed followed by washing with tap and then distilled
Evidence-Based Complementary and Alternative Medicine 3
water Sections were then stained to identify nuclei withRegaud or Weigert hematoxylin for 5ndash10min After fullywashing with water slides were washed with distilled waterand treated with Ponceau Masson Acid fuchsin solutionfor 5ndash10min Sections were then briefly immersed in a 2aqueous acetic acid solution and then treated with 1 phos-phomolybdic acid for 3ndash5min followed by direct stainingwith aniline blue or light green liquid dye for 5min Aftera brief Immersion in 02 acetic acid sections were treatedwith 95 alcohol ethanol and transparent xylene and thencemented with neutral gum For each slice six fields (under200x magnification) were selected Positive Masson stainingfor collagen depositionwas analyzed using by Image-Pro Plusmultimedia color pathological image analysis software Theratio of collagen deposition to the viewed area was calculatedand averaged
27 KGFandHMGB1Expression in LungTissue Keratinocytegrowth factor (KGF) antibody was purchased from Biorbyt(Cambridge UK) and the immunohistochemistry kit wasfrom Gene Technology (Shanghai China) High mobilitygroup box 1 protein (HMGB1) antibody was purchasedfrom Santa Cruz Biotechnology (Santa Cruz CA) andthe immunohistochemistry kit was from Gene Technology(Shanghai China) Lung tissue sections were deparaffinizedaccording to kit instructions and then stained with hema-toxylin and viewed with light microscopy Images wereanalyzed with Media Cybernetics Image-Pro Plus imageanalysis software Each slice was assessed using 6 fields ofintegrated optical density (IOD) which represented proteinexpression
28 Measurement of Inflammatory Mediators and sIgA byELISA The sacrificed mice were placed in a supine positionand perfused with two 075ml aliquots of ice-cold normalsaline (NS) Each animal was lavaged five times Lavage fluidwas collected and the cellular contents and bronchoalveolarlavage (BAL) fluid were separated by centrifugation Super-natant was used to measure secretory immunoglobulin A(sIgA) with enzyme-linked immunosorbent assay (ELISA)kits (Abbexa Cambridge UK) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)
Lung tissue (01 g) was placed in a 15ml EP tube toprepare 10 lung homogenate Homogenate was centrifugedat 12000 rpm and 4∘C for 20min Supernatant used tomeasure inflammatory mediators from interleukin-4 (IL-4) interleukin-6 (IL-6) interleukin-10 (IL-10) interleukin-17 (IL-17) interleukin-1120573 (IL-1120573) and tumor necrosis factor(TNF-120572) with enzyme-linked immunosorbent assay (ELISA)kits (R amp D Minneapolis MN) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)
29 Real-Time Reverse Transcriptase Polymerase Chain Reac-tion (RT-PCR) RT-PCR was used to measure IL-8 and IgAexpression in mouse lung tissues Total RNA was extractedfrom 100mg lung tissuewithTrizol after a one-step extraction
Table 1 PM25-related diseases identified through Polysearch
Number 119885 score Disease name1 9 Respiratory disease2 81 Asthma3 77 Lung cancer4 58 Cardiovascular disease5 37 COPD6 22 Atherosclerosis7 12 Ischemic stroke8 08 Pneumonia9 07 Gestational diabetes mellitus10 07 Pulmonary embolism
protocol cDNA was synthesized by reverse transcriptionwith 2120583g RNA 1 120583l oligo (dT) and DEPC water and 12 120583llung tissue 120573-Actin primer sequence is as follows forwardprimer 51015840-GTGACGTTGACATCCGTAAAGA-31015840 and thereverse primer 51015840-GTAACAGTCCGCCTAGAAGCAC-31015840IL-8 primer sequence is as follows forward primer 51015840-CATCTTCGTCCGTCCCTGTG-31015840 and reverse primer 51015840-GCCAACAGTAGCCTTCACCCA-31015840 IgA primer sequenceis as follows forward primer 51015840-GCTACAGTGTGTCCA-GCGTCCT-31015840 and reverse primer 51015840-TGCCAGACTCAG-GATGGGTAAC-31015840 Quantitative analysis was performedusing the 2minusΔΔCt method
3 Statistics
Data are represented as means plusmn standard deviation Sta-tistical analysis was conducted with SPSS 170 softwareComparisons among multiple groups were analyzed withone-way ANOVA with a Tukey-Kramer post hoc correctionSingle comparisons were made with an unpaired two-tailedStudentrsquos 119905-test Differences were considered statistically sig-nificant if 119901 lt 005
4 Results
41 PM25-Related Disease Prioritization and Predicted Tar-gets Polysearch platform analysis yielded a list of PM25related diseases (Table 1) which were prioritized based ona relevancy score and expressed as a 119885 score which refersto the number of standard deviations of the relevancy scoreabove the mean value A higher 119885 score denotes a lesserlikelihood that the outcome is due to chance Polysearchplatform queries confirmed that 98 10 and 9 target proteinswere associated with Astragalus radix paeoniae rubra andPsoralea corylifolia respectively (Figures 1ndash5)
42 Effect of BFHX on Mouse Pulmonary Function Com-pared with controls lung inspiratory and expiratory resis-tances were significantly greater (119901 lt 001 119901 lt 005)in PM25 mice Airway compliance and maximum forcedexpiratory flow were less in PM25 mice BFHX intervention
4 Evidence-Based Complementary and Alternative Medicine
HMOXLTB4DH CA1 BALp38
TelomeraseSuccinate
dehydrogenase(protein family
or complex) TGFB1 VEGF
TIMP1
ornithinedecarboxylase
ioredoxin
PHT1
albumin
5lipoxygenase
acetylcholinereceptor
AMPK
AS160Radixpaeoniaerubra
MAPK
Bcl2
T bet
Superoxidedismutase
Notch1NFATc3
ATPase PI3KAT2
p65
complementC3
ATF6
P glycoprotein
BFGF
PARP
IL10
CXCL12
CATCYP3A4
EC-NOSCyclin
dependentkinases
(protein family or complex)
G-CSF
Heparanase
TG2
Gracile
VCAM1 keap1
aFGFALDR
TyrosinaseTNFR1
A10
Sirtuin 1TRPA1
TSLPIL17 IL13ABPA
B7H3AdiponectinIgE
BDNFPeriostinBeta CateninVisfatin
Psoraleacorylifolia
Monoamineoxidases
CES1
Smoothmuscle actin
complex I CASP3 CYC
ERA
PTP1BCalcineurin
(protein family or complex)
CD35PPARA CCL2
Protein kinase D1
CD45
PSAP CCR5CD11c
SERCA2 AGT JNK3CD8 CCL5IL8
SAPS
LDHMMP1IL2
Pyrophosphatase
PPARG Myostatin IFNgammaAstragalus
c Jun N terminalkinase
PendrinICAM1SulfatetransportersCaspase 3
N33IL4
MLCK
MicroRNA
IL6
LAMA
TNFA IVF
CD4
CD25
Statins Myosin
STAT1
STAT3
MMP2MMP9
MTL4MUC1
NPYIL1B
Calpain(protein family
or complex)
IL18
IL12
TLR4CAPE
IL15
MTHFR
CD69
ImmunoglobulinIL5
Interleukins
IL33 IL17F CC16ADAM33
HMGB1HASC
GATA3
GAP43
PBE
ORMDL3
CTLA4
Chitinase
5lipoxygenaseCD86
EGFR
Asthma
Interleukin 5
MicroRNAsChymase
proteinTyrosine
phosphatase
Figure 1 Potential targets of BFHX in asthma Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents asthma round blue nodes represent drug targets red nodes represent drug targets of disease
P53 MTHFR MicroRNAs
EML4EGFR
E cadherin
Lung cancer
CYP4502A6
p21 protein
Fascin
B7H1
PTEN
HER2
Beta catenin
KRAS
LUNX
MALAT1
MDM2 c Myc
GSTT1
CHRNA5
CHRNA3
GSTP1
CEACAM5
CDK2
HSP90AB1
CD133CXCR4
CYP1B1
CYP2E1
FBP1
GSTM1
IL10
Bcl2
MAPK
MMP9
STAT3
MMP2
TERT
STK11
SCLC
ROS1
RASSF1A
TRAF6
HMOX
Radixpaeoniaerubra
BALLTB4DH
CD35
Calpain(protein family
or complex)
P glycoprotein
CD8
Chymase
CCR5
CD69
Cyclindependentkinases
(protein family or complex)
c Jun N terminalkinase
AS160
Albumin
AMPK
ALDR
CD11c
IL18
Heparanase
Gracile
IL1B
G-CSF
MUC1
CD25
MTL4
CYP3A4
N33
JNK3
Astragalus
ICAM1
IL8
Myosin
Myostatin
keap1Interleukin 5
LDH
NFATc3
IL12
TIMP1
TelomeraseTG2
TGFB1
ioredoxin
IFNgamma
Notch1Ornithine
decarboxylase
IL15
PPARA
Superoxidedismutase
Proteintyrosine
phosphatase
PHT1
MicroRNAs
MMP1
ATF6ATPase
EC-NOS
IL2
BFGFPTP1B
Protein kinase D1
Succinatedehydrogenase(protein family
or complex)
Calcineurin(protein family
or complex)
PSAP
SAPS
Pyrophosphatase
SERCA2
IL6
CA1
CASP3
CXCL12
PI3K
CAPETyrosinase
PPARGp65CD4 Statins
STAT1Caspase 3
CD45 CATSulfatetransporters
VCAM1TNFR1
TNFATLR4
T betVEGF
ComplementC3
AGTAT2
CCL5A10
Acetylcholinereceptor
CCL2
5lipoxygenase
aFGF
complex I
Smoothmuscle actin
Psoraleacorylifolia
Monoamineoxidases CYCPARP ERACES1
p38 IL4
WISP1XRCC1
XRCC3ABCB1ALDH1ALK
API4
CLPTM1LVEGFR2 BRAFmiR21IL17
CK19VIMPIK3CA
BCRP
Figure 2 Potential targets of BFHX in lung cancer Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents lung cancer round blue nodes represent drug targets red nodes represent drug targets of disease
significantly decreased inspiratory (119901 lt 001) and expiratoryresistance (119901 lt 005) and increased dynamic lung complianceand maximum forced expiratory flow (119901 lt 001) in PM25mice Thus BFHX intervention significantly improved lungfunction and reduced airway resistance and increased airwaycompliance (Figure 6) in PM25 mice
43 Effect of BFHX on PM25-Induced Pulmonary Histopa-thology in Mice In the normal group and the BFHX groupbronchial mucosa and bronchial wall structures were intactand alveolar structural integrity was intact Some inflam-matory cells had infiltrated alveolar spaces but there waslittle interstitial inflammation and lung capillary structures
were intact with no bleeding Figure 7 shows that com-pared with the normal group and the BFHX group PM25exposure caused histological injury such as widened alveolarsepta capillary congestion and minor hemorrhages of smallairways BFHX treatment significantly reduced histologicalinjury and reduced congestion and hemorrhage of smallairways and recruitment
44 Effect of BFHX on Lung Collagen Deposition in MiceControls had collagen deposition in many small airways andfibrosis was noted around the vascular wall PM25-exposedlung tissues had thickened airways with obvious collagendeposition smaller alveoli with wider septa and obvious
Evidence-Based Complementary and Alternative Medicine 5
NFE2L2
Interleukin
S100B
SERPINA1
SERPINE2
SFTP1
Paraoxonase
MMP20mtTFA
Neutrophilelastase
Acetylcholinereceptors HTR4
GATA3
IL13
MicroRNAsMMP12
LAMALeptin
GSTP1
GSTM1
CHRNA5
CHRNA3
Chemokines
CFTR
HMGB1OPG
Hemoglobin
GSTT1ElastinFOXP3
IL17
HHIP
HD2
IREB2
COPD
EGR1
CXCR2
CYP1A1
EGLN2
EGFR
Immunoglobulin
PDE4A
IL33
IL32
IL22
MMP9
TIMP1
MAPK
p38
IL8
IL1B
IL6
IL10
VEGF
PI3K
Ornithinedecarboxylase
IFNgamma
Tyrosinase
MMP2
Acetylcholinereceptor
AMPK
EC-NOS
CYP3A4
AT2MUC1Myosin
MyostatinN33
Calpain(protein family
or complex) chymase
c Jun N terminalKinase
ATPase
Calcineurin(protein family
or complex)
CD35
CD25
CD45BFGF
CD69
complementC3
AstragalusVCAM1
Succinatedehydrogenase(protein family
or complex)
CD11cATF6
G-CSF
IL18Heparanase
ICAM1IL12IL15IL2
Gracile
P glycoprotein
Notch1
Superoxidedismutase
NFATc3
PHT1
PTP1B
Pyrophosphatase
PSAP
protein kinase D1
5lipoxygenase
JNK3
PPARG
PPARA
Interleukin 5
SAPS
LDH
MicroRNAs
PTX3
SOCS3
TRAIL
ROR1SPD
RAGE
Surfactantprotein B
Sirtuin1
CD11b
CCSP
CTRP5
CTLA4
Cyclindependent
kinases(protein family
or complex) AS160
CCR5CCL5
CCL2CATCaspase 3
CA1CXCL12
BAL
IL4LTB4DH Bcl2
Sulfatetransporters
MTL4 keap1
STAT3
CAPE
Proteintyrosine
phosphatase
A10
p65
TGFB1ioredoxin
STAT1
TNFR1TLR4
ALDR
aFGFAGT
Albumin
MMP1
Smoothmuscle actin
PARP
CASP3ERA
CYC
Monoamineoxidases
complex I
CES1HMOX
CD8
TelomeraseCD4
SERCA2TNFA
T bet
TG2Statins
ADAM33IgEACHE
XRCC5
S100A4
Ubiquitin
CPAP
VDB
COX2
Adiponectin
BD1CRP
AQP5
CST3
BAFF
ADRB2 Radixpaeoniae
rubraPsoraleacorylifolia
Figure 3 Potential targets of BFHX in COPD Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents COPD round blue nodes represent drug targets red nodes represent drug targets of disease
GAP
AD7
gp91phox
ADAM33
GBP5
ADPRTADAM28
ADAM10
Gal3Phe3
TREM1
PAG1
UPA
PFGE
ACHEVWF
Ferritin
AD3
PIGN
ASCABPA
Fatty acid bindingprotein Transferrin
ZFP36L1
C10CA125
Chitinase 3 like 1 COPD6 Pneumonia
CPAP
BDNFHAP
HCAP Bradykinin
HELIOS AvianB99ARG1
FER
CD86
ChitinaseCFTR
CVID
CSF2CTLA3CTRL CMH7COLEC7CRP
CTSS
IMP 1ImportinIPS
ImmunoglobulinKidsK20
IRF5Interleukins
O13
NOD2NTMProgranulin Interferon
PPTOSM
IL25
PRSPPAI1
PLEKHA7 p42P2Y2Prothrombin
BALLTB4DHCA1
IL1B
HMOXCXCL12
TNFA
Acetylcholinereceptor
IL12
VEGF
IL8
CD4
STAT3
Statins
TGFB1
Telomerase
PPARG
Succinatedehydrogenase
(proteinfamily or complex)
T bet Proteinkinase D1
ioredoxin
p38
TIMP1
PTP1BTG2
SERCA2
SAPS
Superoxidedismutase
Sulfatetransporters
Cyclindependent
kinases(proteinfamily or complex)
STAT1
Pyrophosphatase
NFATc3
PHT1
CD69p65
Ornithinedecarboxylase
Chymase
PGlycoprotein
Notch1N33
LDH
TNFR1
IL18Interleukin 5
CD8
PSAP
CYP3A4
PI3K
PPARA
Myosin
EC-NOS
IL4
IL10AGT
IL6
TLR4
PSA
PTX3PSPC
REL
Q10RAGE
PSPB
SCT
SPIN
SCAP
SFTPA2
SOD
SCCA
SIGIRR
SARS
SAPS2
SCIN
Lipocalin 2
MAPK
MAC387
LEPR
MBL
MDP
ST2TFI
MLKL
Endoglin
Tie2
MincleETT
MRP8P97
MPO
rombomodulin
TPATR
TLR9
TLR1TLR2
TRAF6
DHPS
CXCL5
DHRS2
CXCL2
ELA2
CytolysinCYLD
EGFR
DHFR
RIP1
LAMP
LAMA
CXCL1
L12L selectin
RF
SAARIP3
Smoothmuscle
actinCYCComplex I
CASP3PARP
ERAMonoamineoxidases
CES1
ATF6c Jun N
terminalkinase
ComplementC3
AS160AT2
Calcineurin(proteinfamily or complex)BFGF
proteinTyrosine
phosphatase
Myostatin
MMP1CD45MMP2
MMP9
CD35
MTL4MUC1
ICAM1Caspase 3CAPE
Astragalus
ATPase
IFNgamma
TyrosinaseHeparanase
CAT
G-CSF
Gracile
CD11cCCR5
JNK3
CCL2
IL2CCL5
IL15
aFGF
VCAM1
ALDRAlbumin
Bcl2 MAPK
AMPK
5Lipoxygenase
A10
Keap1MicroRNAsCalpain
(proteinfamily or complex)
CD25
HFABP
Heparanase AnnexinsHemopexin Annexin A1
ANX2
CD44CD143
CBG
CABP
CD62
CCCKR4
CalciumChannel
CD64
AFP
AminopeptidaseALB
AHF
ANGPTL2Hemoglobin
HIES
Hla a
HGF
IFNG
ICS
HMGB1
HSPC008
IgE
Musashi1
IL22
ICOS
Neuraminidase
Plasminogen
IL16
Muscles
IL17IL1RA
IL13
HP
APA
HSP72
BNP32
HSP60
ATP12A
AQP4
APOB100
HLAHLADOA
Atg16L1
PsoraleacorylifoliaRadix
paeoniaerubra
DRB1lowast11
Figure 4 Potential targets of BFHX in pneumonia Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents pneumonia round blue nodes represent drug targets red nodes represent drug targets of disease
fibrosis Compared with PM25 lungs BFHX-treated tissuehad less tracheal and lung interstitial fibrosis (Figure 8)ThusBFHX significantly alleviated collagen deposition in PM25mice
45 Effect of BFHX on HMGB1 and KGF Expression inMouse Lung Tissues HMGB1 expression in alveolar tissue
was significantly greater in PM25 tissues compared withcontrols (119901 lt 001) and the BFHX intervention group (119901 lt001 Figures 9(a) and 9(c)) suggesting reduced inflammationwas due to BFHX Also in lung tissue of PM25-exposedanimals KGF expression in tracheal mucosa and alveolartissue was significantly greater than in normal mice and theBFHX intervention group (119901 lt 005 Figures 9(b) and 9(d))
6 Evidence-Based Complementary and Alternative Medicine
HFABP
HMOX1Integrin
HaptoglobinHemoglobin
IFB BAL
IL10 p38
LTB4DH CA1HMOX
MAPK
CXCL12
IL4Bcl2
Pulmonary
embolism
cTnI
ASPS
CXCL4FGFR2
CRAT
CD309
ERA
PARPCYC
Complex I
CASP3
Monoamine
Smoothmuscle actin
CES1
VEGF
Albumin
Statins
IL6
CYP3A4
PSAP
BET1
ADM
APE
ANPB
ACPAArginase
FX
APC
CTPA
cTnT
Interferon
CRP
ARF
APS
ARG2
APOE
GPVI
CYP2C9
FDG
GGT
ADAMTS13
TIMP1
Proteintyrosine
phosphatase
Superoxidedismutase
Succinatedehydrogenase(protein family
or complex)
ioredoxin
TG2
BMPR2BNP
CD62
CD62E
PLJAMA
PAI1
Interleukins
Factor VIIa
MicroRNA134MMP20
MTHFR
SERPINC1
PVAPROS
SMARCAL1
Plasminogen
SCUBE1
PROC
NOS3
NPSA
PERC
Methemoglobin
Immunoglobulin
TPA
SERPINA1
SPARrombin
romboplastin
VKORC1
VV
PASP
Muscles
PATE
JAK2
KS1
TNFA
5lipoxygenase
PPARG
TNFR1Tyrosinase
PPARA
VCAM1
aFGF
Caspase 3MMP9
ATPase
IL8
Heparanase
Interleukin 5BFGF
Astragalus
IL2
PTP1B
ICAM1STAT1
SERCA2
MMP2PI3K
MMP1
G-CSF SAPS
Gracile
c Jun N terminalkinase
Calcineurin(protein family
or complex)
AS160
AGT
Calpain(protein family
or complex) ALDR
Acetylcholinereceptor
AMPK
A10
STAT3IL1B
ATF6
keap1T bet
ComplementC3
IL12
IL18CD45 AT2IL15
TelomeraseCCR5
MicroRNAs
CCL5
LDH
Ornithinedecarboxylase
NFATc3
CD11c
Notch1
CD35
P glycoprotein
Myostatin
CD4
N33 CCL2
MUC1
Cyclindependent
kinases(protein family
or complex) JNK3MTL4
CATMyosin
CAPE
Sulfatetransporters
CD69
Chymase
CD8
PHT1
IFNgamma
EC-NOS
p65
CD25
Protein kinase D1
TLR4
TGFB1Pyrophosphatase
Radixpaeoniae
rubra
oxidases
Psoraleacorylifolia
Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease
Normal Model BFHX00
05
10
15
RL-m
ean
(cm
H2Omiddots
m)
lowastlowast lowastlowast
(a)Normal Model BFHX
00
05
10
15
20
25
lowast lowast
RL-m
ean
(cm
H2Omiddots
m)
(b)
Normal Model BFHX000
002
004
006
Cdy
n-m
ean
(mlc
mH
2O
)
lowastlowast
lowastlowast
(c)Normal Model BFHX
0
1
2
3
PEF
(mls
)
lowast lowastlowast
(d)
Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 3
water Sections were then stained to identify nuclei withRegaud or Weigert hematoxylin for 5ndash10min After fullywashing with water slides were washed with distilled waterand treated with Ponceau Masson Acid fuchsin solutionfor 5ndash10min Sections were then briefly immersed in a 2aqueous acetic acid solution and then treated with 1 phos-phomolybdic acid for 3ndash5min followed by direct stainingwith aniline blue or light green liquid dye for 5min Aftera brief Immersion in 02 acetic acid sections were treatedwith 95 alcohol ethanol and transparent xylene and thencemented with neutral gum For each slice six fields (under200x magnification) were selected Positive Masson stainingfor collagen depositionwas analyzed using by Image-Pro Plusmultimedia color pathological image analysis software Theratio of collagen deposition to the viewed area was calculatedand averaged
27 KGFandHMGB1Expression in LungTissue Keratinocytegrowth factor (KGF) antibody was purchased from Biorbyt(Cambridge UK) and the immunohistochemistry kit wasfrom Gene Technology (Shanghai China) High mobilitygroup box 1 protein (HMGB1) antibody was purchasedfrom Santa Cruz Biotechnology (Santa Cruz CA) andthe immunohistochemistry kit was from Gene Technology(Shanghai China) Lung tissue sections were deparaffinizedaccording to kit instructions and then stained with hema-toxylin and viewed with light microscopy Images wereanalyzed with Media Cybernetics Image-Pro Plus imageanalysis software Each slice was assessed using 6 fields ofintegrated optical density (IOD) which represented proteinexpression
28 Measurement of Inflammatory Mediators and sIgA byELISA The sacrificed mice were placed in a supine positionand perfused with two 075ml aliquots of ice-cold normalsaline (NS) Each animal was lavaged five times Lavage fluidwas collected and the cellular contents and bronchoalveolarlavage (BAL) fluid were separated by centrifugation Super-natant was used to measure secretory immunoglobulin A(sIgA) with enzyme-linked immunosorbent assay (ELISA)kits (Abbexa Cambridge UK) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)
Lung tissue (01 g) was placed in a 15ml EP tube toprepare 10 lung homogenate Homogenate was centrifugedat 12000 rpm and 4∘C for 20min Supernatant used tomeasure inflammatory mediators from interleukin-4 (IL-4) interleukin-6 (IL-6) interleukin-10 (IL-10) interleukin-17 (IL-17) interleukin-1120573 (IL-1120573) and tumor necrosis factor(TNF-120572) with enzyme-linked immunosorbent assay (ELISA)kits (R amp D Minneapolis MN) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)
29 Real-Time Reverse Transcriptase Polymerase Chain Reac-tion (RT-PCR) RT-PCR was used to measure IL-8 and IgAexpression in mouse lung tissues Total RNA was extractedfrom 100mg lung tissuewithTrizol after a one-step extraction
Table 1 PM25-related diseases identified through Polysearch
Number 119885 score Disease name1 9 Respiratory disease2 81 Asthma3 77 Lung cancer4 58 Cardiovascular disease5 37 COPD6 22 Atherosclerosis7 12 Ischemic stroke8 08 Pneumonia9 07 Gestational diabetes mellitus10 07 Pulmonary embolism
protocol cDNA was synthesized by reverse transcriptionwith 2120583g RNA 1 120583l oligo (dT) and DEPC water and 12 120583llung tissue 120573-Actin primer sequence is as follows forwardprimer 51015840-GTGACGTTGACATCCGTAAAGA-31015840 and thereverse primer 51015840-GTAACAGTCCGCCTAGAAGCAC-31015840IL-8 primer sequence is as follows forward primer 51015840-CATCTTCGTCCGTCCCTGTG-31015840 and reverse primer 51015840-GCCAACAGTAGCCTTCACCCA-31015840 IgA primer sequenceis as follows forward primer 51015840-GCTACAGTGTGTCCA-GCGTCCT-31015840 and reverse primer 51015840-TGCCAGACTCAG-GATGGGTAAC-31015840 Quantitative analysis was performedusing the 2minusΔΔCt method
3 Statistics
Data are represented as means plusmn standard deviation Sta-tistical analysis was conducted with SPSS 170 softwareComparisons among multiple groups were analyzed withone-way ANOVA with a Tukey-Kramer post hoc correctionSingle comparisons were made with an unpaired two-tailedStudentrsquos 119905-test Differences were considered statistically sig-nificant if 119901 lt 005
4 Results
41 PM25-Related Disease Prioritization and Predicted Tar-gets Polysearch platform analysis yielded a list of PM25related diseases (Table 1) which were prioritized based ona relevancy score and expressed as a 119885 score which refersto the number of standard deviations of the relevancy scoreabove the mean value A higher 119885 score denotes a lesserlikelihood that the outcome is due to chance Polysearchplatform queries confirmed that 98 10 and 9 target proteinswere associated with Astragalus radix paeoniae rubra andPsoralea corylifolia respectively (Figures 1ndash5)
42 Effect of BFHX on Mouse Pulmonary Function Com-pared with controls lung inspiratory and expiratory resis-tances were significantly greater (119901 lt 001 119901 lt 005)in PM25 mice Airway compliance and maximum forcedexpiratory flow were less in PM25 mice BFHX intervention
4 Evidence-Based Complementary and Alternative Medicine
HMOXLTB4DH CA1 BALp38
TelomeraseSuccinate
dehydrogenase(protein family
or complex) TGFB1 VEGF
TIMP1
ornithinedecarboxylase
ioredoxin
PHT1
albumin
5lipoxygenase
acetylcholinereceptor
AMPK
AS160Radixpaeoniaerubra
MAPK
Bcl2
T bet
Superoxidedismutase
Notch1NFATc3
ATPase PI3KAT2
p65
complementC3
ATF6
P glycoprotein
BFGF
PARP
IL10
CXCL12
CATCYP3A4
EC-NOSCyclin
dependentkinases
(protein family or complex)
G-CSF
Heparanase
TG2
Gracile
VCAM1 keap1
aFGFALDR
TyrosinaseTNFR1
A10
Sirtuin 1TRPA1
TSLPIL17 IL13ABPA
B7H3AdiponectinIgE
BDNFPeriostinBeta CateninVisfatin
Psoraleacorylifolia
Monoamineoxidases
CES1
Smoothmuscle actin
complex I CASP3 CYC
ERA
PTP1BCalcineurin
(protein family or complex)
CD35PPARA CCL2
Protein kinase D1
CD45
PSAP CCR5CD11c
SERCA2 AGT JNK3CD8 CCL5IL8
SAPS
LDHMMP1IL2
Pyrophosphatase
PPARG Myostatin IFNgammaAstragalus
c Jun N terminalkinase
PendrinICAM1SulfatetransportersCaspase 3
N33IL4
MLCK
MicroRNA
IL6
LAMA
TNFA IVF
CD4
CD25
Statins Myosin
STAT1
STAT3
MMP2MMP9
MTL4MUC1
NPYIL1B
Calpain(protein family
or complex)
IL18
IL12
TLR4CAPE
IL15
MTHFR
CD69
ImmunoglobulinIL5
Interleukins
IL33 IL17F CC16ADAM33
HMGB1HASC
GATA3
GAP43
PBE
ORMDL3
CTLA4
Chitinase
5lipoxygenaseCD86
EGFR
Asthma
Interleukin 5
MicroRNAsChymase
proteinTyrosine
phosphatase
Figure 1 Potential targets of BFHX in asthma Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents asthma round blue nodes represent drug targets red nodes represent drug targets of disease
P53 MTHFR MicroRNAs
EML4EGFR
E cadherin
Lung cancer
CYP4502A6
p21 protein
Fascin
B7H1
PTEN
HER2
Beta catenin
KRAS
LUNX
MALAT1
MDM2 c Myc
GSTT1
CHRNA5
CHRNA3
GSTP1
CEACAM5
CDK2
HSP90AB1
CD133CXCR4
CYP1B1
CYP2E1
FBP1
GSTM1
IL10
Bcl2
MAPK
MMP9
STAT3
MMP2
TERT
STK11
SCLC
ROS1
RASSF1A
TRAF6
HMOX
Radixpaeoniaerubra
BALLTB4DH
CD35
Calpain(protein family
or complex)
P glycoprotein
CD8
Chymase
CCR5
CD69
Cyclindependentkinases
(protein family or complex)
c Jun N terminalkinase
AS160
Albumin
AMPK
ALDR
CD11c
IL18
Heparanase
Gracile
IL1B
G-CSF
MUC1
CD25
MTL4
CYP3A4
N33
JNK3
Astragalus
ICAM1
IL8
Myosin
Myostatin
keap1Interleukin 5
LDH
NFATc3
IL12
TIMP1
TelomeraseTG2
TGFB1
ioredoxin
IFNgamma
Notch1Ornithine
decarboxylase
IL15
PPARA
Superoxidedismutase
Proteintyrosine
phosphatase
PHT1
MicroRNAs
MMP1
ATF6ATPase
EC-NOS
IL2
BFGFPTP1B
Protein kinase D1
Succinatedehydrogenase(protein family
or complex)
Calcineurin(protein family
or complex)
PSAP
SAPS
Pyrophosphatase
SERCA2
IL6
CA1
CASP3
CXCL12
PI3K
CAPETyrosinase
PPARGp65CD4 Statins
STAT1Caspase 3
CD45 CATSulfatetransporters
VCAM1TNFR1
TNFATLR4
T betVEGF
ComplementC3
AGTAT2
CCL5A10
Acetylcholinereceptor
CCL2
5lipoxygenase
aFGF
complex I
Smoothmuscle actin
Psoraleacorylifolia
Monoamineoxidases CYCPARP ERACES1
p38 IL4
WISP1XRCC1
XRCC3ABCB1ALDH1ALK
API4
CLPTM1LVEGFR2 BRAFmiR21IL17
CK19VIMPIK3CA
BCRP
Figure 2 Potential targets of BFHX in lung cancer Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents lung cancer round blue nodes represent drug targets red nodes represent drug targets of disease
significantly decreased inspiratory (119901 lt 001) and expiratoryresistance (119901 lt 005) and increased dynamic lung complianceand maximum forced expiratory flow (119901 lt 001) in PM25mice Thus BFHX intervention significantly improved lungfunction and reduced airway resistance and increased airwaycompliance (Figure 6) in PM25 mice
43 Effect of BFHX on PM25-Induced Pulmonary Histopa-thology in Mice In the normal group and the BFHX groupbronchial mucosa and bronchial wall structures were intactand alveolar structural integrity was intact Some inflam-matory cells had infiltrated alveolar spaces but there waslittle interstitial inflammation and lung capillary structures
were intact with no bleeding Figure 7 shows that com-pared with the normal group and the BFHX group PM25exposure caused histological injury such as widened alveolarsepta capillary congestion and minor hemorrhages of smallairways BFHX treatment significantly reduced histologicalinjury and reduced congestion and hemorrhage of smallairways and recruitment
44 Effect of BFHX on Lung Collagen Deposition in MiceControls had collagen deposition in many small airways andfibrosis was noted around the vascular wall PM25-exposedlung tissues had thickened airways with obvious collagendeposition smaller alveoli with wider septa and obvious
Evidence-Based Complementary and Alternative Medicine 5
NFE2L2
Interleukin
S100B
SERPINA1
SERPINE2
SFTP1
Paraoxonase
MMP20mtTFA
Neutrophilelastase
Acetylcholinereceptors HTR4
GATA3
IL13
MicroRNAsMMP12
LAMALeptin
GSTP1
GSTM1
CHRNA5
CHRNA3
Chemokines
CFTR
HMGB1OPG
Hemoglobin
GSTT1ElastinFOXP3
IL17
HHIP
HD2
IREB2
COPD
EGR1
CXCR2
CYP1A1
EGLN2
EGFR
Immunoglobulin
PDE4A
IL33
IL32
IL22
MMP9
TIMP1
MAPK
p38
IL8
IL1B
IL6
IL10
VEGF
PI3K
Ornithinedecarboxylase
IFNgamma
Tyrosinase
MMP2
Acetylcholinereceptor
AMPK
EC-NOS
CYP3A4
AT2MUC1Myosin
MyostatinN33
Calpain(protein family
or complex) chymase
c Jun N terminalKinase
ATPase
Calcineurin(protein family
or complex)
CD35
CD25
CD45BFGF
CD69
complementC3
AstragalusVCAM1
Succinatedehydrogenase(protein family
or complex)
CD11cATF6
G-CSF
IL18Heparanase
ICAM1IL12IL15IL2
Gracile
P glycoprotein
Notch1
Superoxidedismutase
NFATc3
PHT1
PTP1B
Pyrophosphatase
PSAP
protein kinase D1
5lipoxygenase
JNK3
PPARG
PPARA
Interleukin 5
SAPS
LDH
MicroRNAs
PTX3
SOCS3
TRAIL
ROR1SPD
RAGE
Surfactantprotein B
Sirtuin1
CD11b
CCSP
CTRP5
CTLA4
Cyclindependent
kinases(protein family
or complex) AS160
CCR5CCL5
CCL2CATCaspase 3
CA1CXCL12
BAL
IL4LTB4DH Bcl2
Sulfatetransporters
MTL4 keap1
STAT3
CAPE
Proteintyrosine
phosphatase
A10
p65
TGFB1ioredoxin
STAT1
TNFR1TLR4
ALDR
aFGFAGT
Albumin
MMP1
Smoothmuscle actin
PARP
CASP3ERA
CYC
Monoamineoxidases
complex I
CES1HMOX
CD8
TelomeraseCD4
SERCA2TNFA
T bet
TG2Statins
ADAM33IgEACHE
XRCC5
S100A4
Ubiquitin
CPAP
VDB
COX2
Adiponectin
BD1CRP
AQP5
CST3
BAFF
ADRB2 Radixpaeoniae
rubraPsoraleacorylifolia
Figure 3 Potential targets of BFHX in COPD Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents COPD round blue nodes represent drug targets red nodes represent drug targets of disease
GAP
AD7
gp91phox
ADAM33
GBP5
ADPRTADAM28
ADAM10
Gal3Phe3
TREM1
PAG1
UPA
PFGE
ACHEVWF
Ferritin
AD3
PIGN
ASCABPA
Fatty acid bindingprotein Transferrin
ZFP36L1
C10CA125
Chitinase 3 like 1 COPD6 Pneumonia
CPAP
BDNFHAP
HCAP Bradykinin
HELIOS AvianB99ARG1
FER
CD86
ChitinaseCFTR
CVID
CSF2CTLA3CTRL CMH7COLEC7CRP
CTSS
IMP 1ImportinIPS
ImmunoglobulinKidsK20
IRF5Interleukins
O13
NOD2NTMProgranulin Interferon
PPTOSM
IL25
PRSPPAI1
PLEKHA7 p42P2Y2Prothrombin
BALLTB4DHCA1
IL1B
HMOXCXCL12
TNFA
Acetylcholinereceptor
IL12
VEGF
IL8
CD4
STAT3
Statins
TGFB1
Telomerase
PPARG
Succinatedehydrogenase
(proteinfamily or complex)
T bet Proteinkinase D1
ioredoxin
p38
TIMP1
PTP1BTG2
SERCA2
SAPS
Superoxidedismutase
Sulfatetransporters
Cyclindependent
kinases(proteinfamily or complex)
STAT1
Pyrophosphatase
NFATc3
PHT1
CD69p65
Ornithinedecarboxylase
Chymase
PGlycoprotein
Notch1N33
LDH
TNFR1
IL18Interleukin 5
CD8
PSAP
CYP3A4
PI3K
PPARA
Myosin
EC-NOS
IL4
IL10AGT
IL6
TLR4
PSA
PTX3PSPC
REL
Q10RAGE
PSPB
SCT
SPIN
SCAP
SFTPA2
SOD
SCCA
SIGIRR
SARS
SAPS2
SCIN
Lipocalin 2
MAPK
MAC387
LEPR
MBL
MDP
ST2TFI
MLKL
Endoglin
Tie2
MincleETT
MRP8P97
MPO
rombomodulin
TPATR
TLR9
TLR1TLR2
TRAF6
DHPS
CXCL5
DHRS2
CXCL2
ELA2
CytolysinCYLD
EGFR
DHFR
RIP1
LAMP
LAMA
CXCL1
L12L selectin
RF
SAARIP3
Smoothmuscle
actinCYCComplex I
CASP3PARP
ERAMonoamineoxidases
CES1
ATF6c Jun N
terminalkinase
ComplementC3
AS160AT2
Calcineurin(proteinfamily or complex)BFGF
proteinTyrosine
phosphatase
Myostatin
MMP1CD45MMP2
MMP9
CD35
MTL4MUC1
ICAM1Caspase 3CAPE
Astragalus
ATPase
IFNgamma
TyrosinaseHeparanase
CAT
G-CSF
Gracile
CD11cCCR5
JNK3
CCL2
IL2CCL5
IL15
aFGF
VCAM1
ALDRAlbumin
Bcl2 MAPK
AMPK
5Lipoxygenase
A10
Keap1MicroRNAsCalpain
(proteinfamily or complex)
CD25
HFABP
Heparanase AnnexinsHemopexin Annexin A1
ANX2
CD44CD143
CBG
CABP
CD62
CCCKR4
CalciumChannel
CD64
AFP
AminopeptidaseALB
AHF
ANGPTL2Hemoglobin
HIES
Hla a
HGF
IFNG
ICS
HMGB1
HSPC008
IgE
Musashi1
IL22
ICOS
Neuraminidase
Plasminogen
IL16
Muscles
IL17IL1RA
IL13
HP
APA
HSP72
BNP32
HSP60
ATP12A
AQP4
APOB100
HLAHLADOA
Atg16L1
PsoraleacorylifoliaRadix
paeoniaerubra
DRB1lowast11
Figure 4 Potential targets of BFHX in pneumonia Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents pneumonia round blue nodes represent drug targets red nodes represent drug targets of disease
fibrosis Compared with PM25 lungs BFHX-treated tissuehad less tracheal and lung interstitial fibrosis (Figure 8)ThusBFHX significantly alleviated collagen deposition in PM25mice
45 Effect of BFHX on HMGB1 and KGF Expression inMouse Lung Tissues HMGB1 expression in alveolar tissue
was significantly greater in PM25 tissues compared withcontrols (119901 lt 001) and the BFHX intervention group (119901 lt001 Figures 9(a) and 9(c)) suggesting reduced inflammationwas due to BFHX Also in lung tissue of PM25-exposedanimals KGF expression in tracheal mucosa and alveolartissue was significantly greater than in normal mice and theBFHX intervention group (119901 lt 005 Figures 9(b) and 9(d))
6 Evidence-Based Complementary and Alternative Medicine
HFABP
HMOX1Integrin
HaptoglobinHemoglobin
IFB BAL
IL10 p38
LTB4DH CA1HMOX
MAPK
CXCL12
IL4Bcl2
Pulmonary
embolism
cTnI
ASPS
CXCL4FGFR2
CRAT
CD309
ERA
PARPCYC
Complex I
CASP3
Monoamine
Smoothmuscle actin
CES1
VEGF
Albumin
Statins
IL6
CYP3A4
PSAP
BET1
ADM
APE
ANPB
ACPAArginase
FX
APC
CTPA
cTnT
Interferon
CRP
ARF
APS
ARG2
APOE
GPVI
CYP2C9
FDG
GGT
ADAMTS13
TIMP1
Proteintyrosine
phosphatase
Superoxidedismutase
Succinatedehydrogenase(protein family
or complex)
ioredoxin
TG2
BMPR2BNP
CD62
CD62E
PLJAMA
PAI1
Interleukins
Factor VIIa
MicroRNA134MMP20
MTHFR
SERPINC1
PVAPROS
SMARCAL1
Plasminogen
SCUBE1
PROC
NOS3
NPSA
PERC
Methemoglobin
Immunoglobulin
TPA
SERPINA1
SPARrombin
romboplastin
VKORC1
VV
PASP
Muscles
PATE
JAK2
KS1
TNFA
5lipoxygenase
PPARG
TNFR1Tyrosinase
PPARA
VCAM1
aFGF
Caspase 3MMP9
ATPase
IL8
Heparanase
Interleukin 5BFGF
Astragalus
IL2
PTP1B
ICAM1STAT1
SERCA2
MMP2PI3K
MMP1
G-CSF SAPS
Gracile
c Jun N terminalkinase
Calcineurin(protein family
or complex)
AS160
AGT
Calpain(protein family
or complex) ALDR
Acetylcholinereceptor
AMPK
A10
STAT3IL1B
ATF6
keap1T bet
ComplementC3
IL12
IL18CD45 AT2IL15
TelomeraseCCR5
MicroRNAs
CCL5
LDH
Ornithinedecarboxylase
NFATc3
CD11c
Notch1
CD35
P glycoprotein
Myostatin
CD4
N33 CCL2
MUC1
Cyclindependent
kinases(protein family
or complex) JNK3MTL4
CATMyosin
CAPE
Sulfatetransporters
CD69
Chymase
CD8
PHT1
IFNgamma
EC-NOS
p65
CD25
Protein kinase D1
TLR4
TGFB1Pyrophosphatase
Radixpaeoniae
rubra
oxidases
Psoraleacorylifolia
Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease
Normal Model BFHX00
05
10
15
RL-m
ean
(cm
H2Omiddots
m)
lowastlowast lowastlowast
(a)Normal Model BFHX
00
05
10
15
20
25
lowast lowast
RL-m
ean
(cm
H2Omiddots
m)
(b)
Normal Model BFHX000
002
004
006
Cdy
n-m
ean
(mlc
mH
2O
)
lowastlowast
lowastlowast
(c)Normal Model BFHX
0
1
2
3
PEF
(mls
)
lowast lowastlowast
(d)
Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
4 Evidence-Based Complementary and Alternative Medicine
HMOXLTB4DH CA1 BALp38
TelomeraseSuccinate
dehydrogenase(protein family
or complex) TGFB1 VEGF
TIMP1
ornithinedecarboxylase
ioredoxin
PHT1
albumin
5lipoxygenase
acetylcholinereceptor
AMPK
AS160Radixpaeoniaerubra
MAPK
Bcl2
T bet
Superoxidedismutase
Notch1NFATc3
ATPase PI3KAT2
p65
complementC3
ATF6
P glycoprotein
BFGF
PARP
IL10
CXCL12
CATCYP3A4
EC-NOSCyclin
dependentkinases
(protein family or complex)
G-CSF
Heparanase
TG2
Gracile
VCAM1 keap1
aFGFALDR
TyrosinaseTNFR1
A10
Sirtuin 1TRPA1
TSLPIL17 IL13ABPA
B7H3AdiponectinIgE
BDNFPeriostinBeta CateninVisfatin
Psoraleacorylifolia
Monoamineoxidases
CES1
Smoothmuscle actin
complex I CASP3 CYC
ERA
PTP1BCalcineurin
(protein family or complex)
CD35PPARA CCL2
Protein kinase D1
CD45
PSAP CCR5CD11c
SERCA2 AGT JNK3CD8 CCL5IL8
SAPS
LDHMMP1IL2
Pyrophosphatase
PPARG Myostatin IFNgammaAstragalus
c Jun N terminalkinase
PendrinICAM1SulfatetransportersCaspase 3
N33IL4
MLCK
MicroRNA
IL6
LAMA
TNFA IVF
CD4
CD25
Statins Myosin
STAT1
STAT3
MMP2MMP9
MTL4MUC1
NPYIL1B
Calpain(protein family
or complex)
IL18
IL12
TLR4CAPE
IL15
MTHFR
CD69
ImmunoglobulinIL5
Interleukins
IL33 IL17F CC16ADAM33
HMGB1HASC
GATA3
GAP43
PBE
ORMDL3
CTLA4
Chitinase
5lipoxygenaseCD86
EGFR
Asthma
Interleukin 5
MicroRNAsChymase
proteinTyrosine
phosphatase
Figure 1 Potential targets of BFHX in asthma Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents asthma round blue nodes represent drug targets red nodes represent drug targets of disease
P53 MTHFR MicroRNAs
EML4EGFR
E cadherin
Lung cancer
CYP4502A6
p21 protein
Fascin
B7H1
PTEN
HER2
Beta catenin
KRAS
LUNX
MALAT1
MDM2 c Myc
GSTT1
CHRNA5
CHRNA3
GSTP1
CEACAM5
CDK2
HSP90AB1
CD133CXCR4
CYP1B1
CYP2E1
FBP1
GSTM1
IL10
Bcl2
MAPK
MMP9
STAT3
MMP2
TERT
STK11
SCLC
ROS1
RASSF1A
TRAF6
HMOX
Radixpaeoniaerubra
BALLTB4DH
CD35
Calpain(protein family
or complex)
P glycoprotein
CD8
Chymase
CCR5
CD69
Cyclindependentkinases
(protein family or complex)
c Jun N terminalkinase
AS160
Albumin
AMPK
ALDR
CD11c
IL18
Heparanase
Gracile
IL1B
G-CSF
MUC1
CD25
MTL4
CYP3A4
N33
JNK3
Astragalus
ICAM1
IL8
Myosin
Myostatin
keap1Interleukin 5
LDH
NFATc3
IL12
TIMP1
TelomeraseTG2
TGFB1
ioredoxin
IFNgamma
Notch1Ornithine
decarboxylase
IL15
PPARA
Superoxidedismutase
Proteintyrosine
phosphatase
PHT1
MicroRNAs
MMP1
ATF6ATPase
EC-NOS
IL2
BFGFPTP1B
Protein kinase D1
Succinatedehydrogenase(protein family
or complex)
Calcineurin(protein family
or complex)
PSAP
SAPS
Pyrophosphatase
SERCA2
IL6
CA1
CASP3
CXCL12
PI3K
CAPETyrosinase
PPARGp65CD4 Statins
STAT1Caspase 3
CD45 CATSulfatetransporters
VCAM1TNFR1
TNFATLR4
T betVEGF
ComplementC3
AGTAT2
CCL5A10
Acetylcholinereceptor
CCL2
5lipoxygenase
aFGF
complex I
Smoothmuscle actin
Psoraleacorylifolia
Monoamineoxidases CYCPARP ERACES1
p38 IL4
WISP1XRCC1
XRCC3ABCB1ALDH1ALK
API4
CLPTM1LVEGFR2 BRAFmiR21IL17
CK19VIMPIK3CA
BCRP
Figure 2 Potential targets of BFHX in lung cancer Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents lung cancer round blue nodes represent drug targets red nodes represent drug targets of disease
significantly decreased inspiratory (119901 lt 001) and expiratoryresistance (119901 lt 005) and increased dynamic lung complianceand maximum forced expiratory flow (119901 lt 001) in PM25mice Thus BFHX intervention significantly improved lungfunction and reduced airway resistance and increased airwaycompliance (Figure 6) in PM25 mice
43 Effect of BFHX on PM25-Induced Pulmonary Histopa-thology in Mice In the normal group and the BFHX groupbronchial mucosa and bronchial wall structures were intactand alveolar structural integrity was intact Some inflam-matory cells had infiltrated alveolar spaces but there waslittle interstitial inflammation and lung capillary structures
were intact with no bleeding Figure 7 shows that com-pared with the normal group and the BFHX group PM25exposure caused histological injury such as widened alveolarsepta capillary congestion and minor hemorrhages of smallairways BFHX treatment significantly reduced histologicalinjury and reduced congestion and hemorrhage of smallairways and recruitment
44 Effect of BFHX on Lung Collagen Deposition in MiceControls had collagen deposition in many small airways andfibrosis was noted around the vascular wall PM25-exposedlung tissues had thickened airways with obvious collagendeposition smaller alveoli with wider septa and obvious
Evidence-Based Complementary and Alternative Medicine 5
NFE2L2
Interleukin
S100B
SERPINA1
SERPINE2
SFTP1
Paraoxonase
MMP20mtTFA
Neutrophilelastase
Acetylcholinereceptors HTR4
GATA3
IL13
MicroRNAsMMP12
LAMALeptin
GSTP1
GSTM1
CHRNA5
CHRNA3
Chemokines
CFTR
HMGB1OPG
Hemoglobin
GSTT1ElastinFOXP3
IL17
HHIP
HD2
IREB2
COPD
EGR1
CXCR2
CYP1A1
EGLN2
EGFR
Immunoglobulin
PDE4A
IL33
IL32
IL22
MMP9
TIMP1
MAPK
p38
IL8
IL1B
IL6
IL10
VEGF
PI3K
Ornithinedecarboxylase
IFNgamma
Tyrosinase
MMP2
Acetylcholinereceptor
AMPK
EC-NOS
CYP3A4
AT2MUC1Myosin
MyostatinN33
Calpain(protein family
or complex) chymase
c Jun N terminalKinase
ATPase
Calcineurin(protein family
or complex)
CD35
CD25
CD45BFGF
CD69
complementC3
AstragalusVCAM1
Succinatedehydrogenase(protein family
or complex)
CD11cATF6
G-CSF
IL18Heparanase
ICAM1IL12IL15IL2
Gracile
P glycoprotein
Notch1
Superoxidedismutase
NFATc3
PHT1
PTP1B
Pyrophosphatase
PSAP
protein kinase D1
5lipoxygenase
JNK3
PPARG
PPARA
Interleukin 5
SAPS
LDH
MicroRNAs
PTX3
SOCS3
TRAIL
ROR1SPD
RAGE
Surfactantprotein B
Sirtuin1
CD11b
CCSP
CTRP5
CTLA4
Cyclindependent
kinases(protein family
or complex) AS160
CCR5CCL5
CCL2CATCaspase 3
CA1CXCL12
BAL
IL4LTB4DH Bcl2
Sulfatetransporters
MTL4 keap1
STAT3
CAPE
Proteintyrosine
phosphatase
A10
p65
TGFB1ioredoxin
STAT1
TNFR1TLR4
ALDR
aFGFAGT
Albumin
MMP1
Smoothmuscle actin
PARP
CASP3ERA
CYC
Monoamineoxidases
complex I
CES1HMOX
CD8
TelomeraseCD4
SERCA2TNFA
T bet
TG2Statins
ADAM33IgEACHE
XRCC5
S100A4
Ubiquitin
CPAP
VDB
COX2
Adiponectin
BD1CRP
AQP5
CST3
BAFF
ADRB2 Radixpaeoniae
rubraPsoraleacorylifolia
Figure 3 Potential targets of BFHX in COPD Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents COPD round blue nodes represent drug targets red nodes represent drug targets of disease
GAP
AD7
gp91phox
ADAM33
GBP5
ADPRTADAM28
ADAM10
Gal3Phe3
TREM1
PAG1
UPA
PFGE
ACHEVWF
Ferritin
AD3
PIGN
ASCABPA
Fatty acid bindingprotein Transferrin
ZFP36L1
C10CA125
Chitinase 3 like 1 COPD6 Pneumonia
CPAP
BDNFHAP
HCAP Bradykinin
HELIOS AvianB99ARG1
FER
CD86
ChitinaseCFTR
CVID
CSF2CTLA3CTRL CMH7COLEC7CRP
CTSS
IMP 1ImportinIPS
ImmunoglobulinKidsK20
IRF5Interleukins
O13
NOD2NTMProgranulin Interferon
PPTOSM
IL25
PRSPPAI1
PLEKHA7 p42P2Y2Prothrombin
BALLTB4DHCA1
IL1B
HMOXCXCL12
TNFA
Acetylcholinereceptor
IL12
VEGF
IL8
CD4
STAT3
Statins
TGFB1
Telomerase
PPARG
Succinatedehydrogenase
(proteinfamily or complex)
T bet Proteinkinase D1
ioredoxin
p38
TIMP1
PTP1BTG2
SERCA2
SAPS
Superoxidedismutase
Sulfatetransporters
Cyclindependent
kinases(proteinfamily or complex)
STAT1
Pyrophosphatase
NFATc3
PHT1
CD69p65
Ornithinedecarboxylase
Chymase
PGlycoprotein
Notch1N33
LDH
TNFR1
IL18Interleukin 5
CD8
PSAP
CYP3A4
PI3K
PPARA
Myosin
EC-NOS
IL4
IL10AGT
IL6
TLR4
PSA
PTX3PSPC
REL
Q10RAGE
PSPB
SCT
SPIN
SCAP
SFTPA2
SOD
SCCA
SIGIRR
SARS
SAPS2
SCIN
Lipocalin 2
MAPK
MAC387
LEPR
MBL
MDP
ST2TFI
MLKL
Endoglin
Tie2
MincleETT
MRP8P97
MPO
rombomodulin
TPATR
TLR9
TLR1TLR2
TRAF6
DHPS
CXCL5
DHRS2
CXCL2
ELA2
CytolysinCYLD
EGFR
DHFR
RIP1
LAMP
LAMA
CXCL1
L12L selectin
RF
SAARIP3
Smoothmuscle
actinCYCComplex I
CASP3PARP
ERAMonoamineoxidases
CES1
ATF6c Jun N
terminalkinase
ComplementC3
AS160AT2
Calcineurin(proteinfamily or complex)BFGF
proteinTyrosine
phosphatase
Myostatin
MMP1CD45MMP2
MMP9
CD35
MTL4MUC1
ICAM1Caspase 3CAPE
Astragalus
ATPase
IFNgamma
TyrosinaseHeparanase
CAT
G-CSF
Gracile
CD11cCCR5
JNK3
CCL2
IL2CCL5
IL15
aFGF
VCAM1
ALDRAlbumin
Bcl2 MAPK
AMPK
5Lipoxygenase
A10
Keap1MicroRNAsCalpain
(proteinfamily or complex)
CD25
HFABP
Heparanase AnnexinsHemopexin Annexin A1
ANX2
CD44CD143
CBG
CABP
CD62
CCCKR4
CalciumChannel
CD64
AFP
AminopeptidaseALB
AHF
ANGPTL2Hemoglobin
HIES
Hla a
HGF
IFNG
ICS
HMGB1
HSPC008
IgE
Musashi1
IL22
ICOS
Neuraminidase
Plasminogen
IL16
Muscles
IL17IL1RA
IL13
HP
APA
HSP72
BNP32
HSP60
ATP12A
AQP4
APOB100
HLAHLADOA
Atg16L1
PsoraleacorylifoliaRadix
paeoniaerubra
DRB1lowast11
Figure 4 Potential targets of BFHX in pneumonia Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents pneumonia round blue nodes represent drug targets red nodes represent drug targets of disease
fibrosis Compared with PM25 lungs BFHX-treated tissuehad less tracheal and lung interstitial fibrosis (Figure 8)ThusBFHX significantly alleviated collagen deposition in PM25mice
45 Effect of BFHX on HMGB1 and KGF Expression inMouse Lung Tissues HMGB1 expression in alveolar tissue
was significantly greater in PM25 tissues compared withcontrols (119901 lt 001) and the BFHX intervention group (119901 lt001 Figures 9(a) and 9(c)) suggesting reduced inflammationwas due to BFHX Also in lung tissue of PM25-exposedanimals KGF expression in tracheal mucosa and alveolartissue was significantly greater than in normal mice and theBFHX intervention group (119901 lt 005 Figures 9(b) and 9(d))
6 Evidence-Based Complementary and Alternative Medicine
HFABP
HMOX1Integrin
HaptoglobinHemoglobin
IFB BAL
IL10 p38
LTB4DH CA1HMOX
MAPK
CXCL12
IL4Bcl2
Pulmonary
embolism
cTnI
ASPS
CXCL4FGFR2
CRAT
CD309
ERA
PARPCYC
Complex I
CASP3
Monoamine
Smoothmuscle actin
CES1
VEGF
Albumin
Statins
IL6
CYP3A4
PSAP
BET1
ADM
APE
ANPB
ACPAArginase
FX
APC
CTPA
cTnT
Interferon
CRP
ARF
APS
ARG2
APOE
GPVI
CYP2C9
FDG
GGT
ADAMTS13
TIMP1
Proteintyrosine
phosphatase
Superoxidedismutase
Succinatedehydrogenase(protein family
or complex)
ioredoxin
TG2
BMPR2BNP
CD62
CD62E
PLJAMA
PAI1
Interleukins
Factor VIIa
MicroRNA134MMP20
MTHFR
SERPINC1
PVAPROS
SMARCAL1
Plasminogen
SCUBE1
PROC
NOS3
NPSA
PERC
Methemoglobin
Immunoglobulin
TPA
SERPINA1
SPARrombin
romboplastin
VKORC1
VV
PASP
Muscles
PATE
JAK2
KS1
TNFA
5lipoxygenase
PPARG
TNFR1Tyrosinase
PPARA
VCAM1
aFGF
Caspase 3MMP9
ATPase
IL8
Heparanase
Interleukin 5BFGF
Astragalus
IL2
PTP1B
ICAM1STAT1
SERCA2
MMP2PI3K
MMP1
G-CSF SAPS
Gracile
c Jun N terminalkinase
Calcineurin(protein family
or complex)
AS160
AGT
Calpain(protein family
or complex) ALDR
Acetylcholinereceptor
AMPK
A10
STAT3IL1B
ATF6
keap1T bet
ComplementC3
IL12
IL18CD45 AT2IL15
TelomeraseCCR5
MicroRNAs
CCL5
LDH
Ornithinedecarboxylase
NFATc3
CD11c
Notch1
CD35
P glycoprotein
Myostatin
CD4
N33 CCL2
MUC1
Cyclindependent
kinases(protein family
or complex) JNK3MTL4
CATMyosin
CAPE
Sulfatetransporters
CD69
Chymase
CD8
PHT1
IFNgamma
EC-NOS
p65
CD25
Protein kinase D1
TLR4
TGFB1Pyrophosphatase
Radixpaeoniae
rubra
oxidases
Psoraleacorylifolia
Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease
Normal Model BFHX00
05
10
15
RL-m
ean
(cm
H2Omiddots
m)
lowastlowast lowastlowast
(a)Normal Model BFHX
00
05
10
15
20
25
lowast lowast
RL-m
ean
(cm
H2Omiddots
m)
(b)
Normal Model BFHX000
002
004
006
Cdy
n-m
ean
(mlc
mH
2O
)
lowastlowast
lowastlowast
(c)Normal Model BFHX
0
1
2
3
PEF
(mls
)
lowast lowastlowast
(d)
Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 5
NFE2L2
Interleukin
S100B
SERPINA1
SERPINE2
SFTP1
Paraoxonase
MMP20mtTFA
Neutrophilelastase
Acetylcholinereceptors HTR4
GATA3
IL13
MicroRNAsMMP12
LAMALeptin
GSTP1
GSTM1
CHRNA5
CHRNA3
Chemokines
CFTR
HMGB1OPG
Hemoglobin
GSTT1ElastinFOXP3
IL17
HHIP
HD2
IREB2
COPD
EGR1
CXCR2
CYP1A1
EGLN2
EGFR
Immunoglobulin
PDE4A
IL33
IL32
IL22
MMP9
TIMP1
MAPK
p38
IL8
IL1B
IL6
IL10
VEGF
PI3K
Ornithinedecarboxylase
IFNgamma
Tyrosinase
MMP2
Acetylcholinereceptor
AMPK
EC-NOS
CYP3A4
AT2MUC1Myosin
MyostatinN33
Calpain(protein family
or complex) chymase
c Jun N terminalKinase
ATPase
Calcineurin(protein family
or complex)
CD35
CD25
CD45BFGF
CD69
complementC3
AstragalusVCAM1
Succinatedehydrogenase(protein family
or complex)
CD11cATF6
G-CSF
IL18Heparanase
ICAM1IL12IL15IL2
Gracile
P glycoprotein
Notch1
Superoxidedismutase
NFATc3
PHT1
PTP1B
Pyrophosphatase
PSAP
protein kinase D1
5lipoxygenase
JNK3
PPARG
PPARA
Interleukin 5
SAPS
LDH
MicroRNAs
PTX3
SOCS3
TRAIL
ROR1SPD
RAGE
Surfactantprotein B
Sirtuin1
CD11b
CCSP
CTRP5
CTLA4
Cyclindependent
kinases(protein family
or complex) AS160
CCR5CCL5
CCL2CATCaspase 3
CA1CXCL12
BAL
IL4LTB4DH Bcl2
Sulfatetransporters
MTL4 keap1
STAT3
CAPE
Proteintyrosine
phosphatase
A10
p65
TGFB1ioredoxin
STAT1
TNFR1TLR4
ALDR
aFGFAGT
Albumin
MMP1
Smoothmuscle actin
PARP
CASP3ERA
CYC
Monoamineoxidases
complex I
CES1HMOX
CD8
TelomeraseCD4
SERCA2TNFA
T bet
TG2Statins
ADAM33IgEACHE
XRCC5
S100A4
Ubiquitin
CPAP
VDB
COX2
Adiponectin
BD1CRP
AQP5
CST3
BAFF
ADRB2 Radixpaeoniae
rubraPsoraleacorylifolia
Figure 3 Potential targets of BFHX in COPD Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents COPD round blue nodes represent drug targets red nodes represent drug targets of disease
GAP
AD7
gp91phox
ADAM33
GBP5
ADPRTADAM28
ADAM10
Gal3Phe3
TREM1
PAG1
UPA
PFGE
ACHEVWF
Ferritin
AD3
PIGN
ASCABPA
Fatty acid bindingprotein Transferrin
ZFP36L1
C10CA125
Chitinase 3 like 1 COPD6 Pneumonia
CPAP
BDNFHAP
HCAP Bradykinin
HELIOS AvianB99ARG1
FER
CD86
ChitinaseCFTR
CVID
CSF2CTLA3CTRL CMH7COLEC7CRP
CTSS
IMP 1ImportinIPS
ImmunoglobulinKidsK20
IRF5Interleukins
O13
NOD2NTMProgranulin Interferon
PPTOSM
IL25
PRSPPAI1
PLEKHA7 p42P2Y2Prothrombin
BALLTB4DHCA1
IL1B
HMOXCXCL12
TNFA
Acetylcholinereceptor
IL12
VEGF
IL8
CD4
STAT3
Statins
TGFB1
Telomerase
PPARG
Succinatedehydrogenase
(proteinfamily or complex)
T bet Proteinkinase D1
ioredoxin
p38
TIMP1
PTP1BTG2
SERCA2
SAPS
Superoxidedismutase
Sulfatetransporters
Cyclindependent
kinases(proteinfamily or complex)
STAT1
Pyrophosphatase
NFATc3
PHT1
CD69p65
Ornithinedecarboxylase
Chymase
PGlycoprotein
Notch1N33
LDH
TNFR1
IL18Interleukin 5
CD8
PSAP
CYP3A4
PI3K
PPARA
Myosin
EC-NOS
IL4
IL10AGT
IL6
TLR4
PSA
PTX3PSPC
REL
Q10RAGE
PSPB
SCT
SPIN
SCAP
SFTPA2
SOD
SCCA
SIGIRR
SARS
SAPS2
SCIN
Lipocalin 2
MAPK
MAC387
LEPR
MBL
MDP
ST2TFI
MLKL
Endoglin
Tie2
MincleETT
MRP8P97
MPO
rombomodulin
TPATR
TLR9
TLR1TLR2
TRAF6
DHPS
CXCL5
DHRS2
CXCL2
ELA2
CytolysinCYLD
EGFR
DHFR
RIP1
LAMP
LAMA
CXCL1
L12L selectin
RF
SAARIP3
Smoothmuscle
actinCYCComplex I
CASP3PARP
ERAMonoamineoxidases
CES1
ATF6c Jun N
terminalkinase
ComplementC3
AS160AT2
Calcineurin(proteinfamily or complex)BFGF
proteinTyrosine
phosphatase
Myostatin
MMP1CD45MMP2
MMP9
CD35
MTL4MUC1
ICAM1Caspase 3CAPE
Astragalus
ATPase
IFNgamma
TyrosinaseHeparanase
CAT
G-CSF
Gracile
CD11cCCR5
JNK3
CCL2
IL2CCL5
IL15
aFGF
VCAM1
ALDRAlbumin
Bcl2 MAPK
AMPK
5Lipoxygenase
A10
Keap1MicroRNAsCalpain
(proteinfamily or complex)
CD25
HFABP
Heparanase AnnexinsHemopexin Annexin A1
ANX2
CD44CD143
CBG
CABP
CD62
CCCKR4
CalciumChannel
CD64
AFP
AminopeptidaseALB
AHF
ANGPTL2Hemoglobin
HIES
Hla a
HGF
IFNG
ICS
HMGB1
HSPC008
IgE
Musashi1
IL22
ICOS
Neuraminidase
Plasminogen
IL16
Muscles
IL17IL1RA
IL13
HP
APA
HSP72
BNP32
HSP60
ATP12A
AQP4
APOB100
HLAHLADOA
Atg16L1
PsoraleacorylifoliaRadix
paeoniaerubra
DRB1lowast11
Figure 4 Potential targets of BFHX in pneumonia Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents pneumonia round blue nodes represent drug targets red nodes represent drug targets of disease
fibrosis Compared with PM25 lungs BFHX-treated tissuehad less tracheal and lung interstitial fibrosis (Figure 8)ThusBFHX significantly alleviated collagen deposition in PM25mice
45 Effect of BFHX on HMGB1 and KGF Expression inMouse Lung Tissues HMGB1 expression in alveolar tissue
was significantly greater in PM25 tissues compared withcontrols (119901 lt 001) and the BFHX intervention group (119901 lt001 Figures 9(a) and 9(c)) suggesting reduced inflammationwas due to BFHX Also in lung tissue of PM25-exposedanimals KGF expression in tracheal mucosa and alveolartissue was significantly greater than in normal mice and theBFHX intervention group (119901 lt 005 Figures 9(b) and 9(d))
6 Evidence-Based Complementary and Alternative Medicine
HFABP
HMOX1Integrin
HaptoglobinHemoglobin
IFB BAL
IL10 p38
LTB4DH CA1HMOX
MAPK
CXCL12
IL4Bcl2
Pulmonary
embolism
cTnI
ASPS
CXCL4FGFR2
CRAT
CD309
ERA
PARPCYC
Complex I
CASP3
Monoamine
Smoothmuscle actin
CES1
VEGF
Albumin
Statins
IL6
CYP3A4
PSAP
BET1
ADM
APE
ANPB
ACPAArginase
FX
APC
CTPA
cTnT
Interferon
CRP
ARF
APS
ARG2
APOE
GPVI
CYP2C9
FDG
GGT
ADAMTS13
TIMP1
Proteintyrosine
phosphatase
Superoxidedismutase
Succinatedehydrogenase(protein family
or complex)
ioredoxin
TG2
BMPR2BNP
CD62
CD62E
PLJAMA
PAI1
Interleukins
Factor VIIa
MicroRNA134MMP20
MTHFR
SERPINC1
PVAPROS
SMARCAL1
Plasminogen
SCUBE1
PROC
NOS3
NPSA
PERC
Methemoglobin
Immunoglobulin
TPA
SERPINA1
SPARrombin
romboplastin
VKORC1
VV
PASP
Muscles
PATE
JAK2
KS1
TNFA
5lipoxygenase
PPARG
TNFR1Tyrosinase
PPARA
VCAM1
aFGF
Caspase 3MMP9
ATPase
IL8
Heparanase
Interleukin 5BFGF
Astragalus
IL2
PTP1B
ICAM1STAT1
SERCA2
MMP2PI3K
MMP1
G-CSF SAPS
Gracile
c Jun N terminalkinase
Calcineurin(protein family
or complex)
AS160
AGT
Calpain(protein family
or complex) ALDR
Acetylcholinereceptor
AMPK
A10
STAT3IL1B
ATF6
keap1T bet
ComplementC3
IL12
IL18CD45 AT2IL15
TelomeraseCCR5
MicroRNAs
CCL5
LDH
Ornithinedecarboxylase
NFATc3
CD11c
Notch1
CD35
P glycoprotein
Myostatin
CD4
N33 CCL2
MUC1
Cyclindependent
kinases(protein family
or complex) JNK3MTL4
CATMyosin
CAPE
Sulfatetransporters
CD69
Chymase
CD8
PHT1
IFNgamma
EC-NOS
p65
CD25
Protein kinase D1
TLR4
TGFB1Pyrophosphatase
Radixpaeoniae
rubra
oxidases
Psoraleacorylifolia
Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease
Normal Model BFHX00
05
10
15
RL-m
ean
(cm
H2Omiddots
m)
lowastlowast lowastlowast
(a)Normal Model BFHX
00
05
10
15
20
25
lowast lowast
RL-m
ean
(cm
H2Omiddots
m)
(b)
Normal Model BFHX000
002
004
006
Cdy
n-m
ean
(mlc
mH
2O
)
lowastlowast
lowastlowast
(c)Normal Model BFHX
0
1
2
3
PEF
(mls
)
lowast lowastlowast
(d)
Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
6 Evidence-Based Complementary and Alternative Medicine
HFABP
HMOX1Integrin
HaptoglobinHemoglobin
IFB BAL
IL10 p38
LTB4DH CA1HMOX
MAPK
CXCL12
IL4Bcl2
Pulmonary
embolism
cTnI
ASPS
CXCL4FGFR2
CRAT
CD309
ERA
PARPCYC
Complex I
CASP3
Monoamine
Smoothmuscle actin
CES1
VEGF
Albumin
Statins
IL6
CYP3A4
PSAP
BET1
ADM
APE
ANPB
ACPAArginase
FX
APC
CTPA
cTnT
Interferon
CRP
ARF
APS
ARG2
APOE
GPVI
CYP2C9
FDG
GGT
ADAMTS13
TIMP1
Proteintyrosine
phosphatase
Superoxidedismutase
Succinatedehydrogenase(protein family
or complex)
ioredoxin
TG2
BMPR2BNP
CD62
CD62E
PLJAMA
PAI1
Interleukins
Factor VIIa
MicroRNA134MMP20
MTHFR
SERPINC1
PVAPROS
SMARCAL1
Plasminogen
SCUBE1
PROC
NOS3
NPSA
PERC
Methemoglobin
Immunoglobulin
TPA
SERPINA1
SPARrombin
romboplastin
VKORC1
VV
PASP
Muscles
PATE
JAK2
KS1
TNFA
5lipoxygenase
PPARG
TNFR1Tyrosinase
PPARA
VCAM1
aFGF
Caspase 3MMP9
ATPase
IL8
Heparanase
Interleukin 5BFGF
Astragalus
IL2
PTP1B
ICAM1STAT1
SERCA2
MMP2PI3K
MMP1
G-CSF SAPS
Gracile
c Jun N terminalkinase
Calcineurin(protein family
or complex)
AS160
AGT
Calpain(protein family
or complex) ALDR
Acetylcholinereceptor
AMPK
A10
STAT3IL1B
ATF6
keap1T bet
ComplementC3
IL12
IL18CD45 AT2IL15
TelomeraseCCR5
MicroRNAs
CCL5
LDH
Ornithinedecarboxylase
NFATc3
CD11c
Notch1
CD35
P glycoprotein
Myostatin
CD4
N33 CCL2
MUC1
Cyclindependent
kinases(protein family
or complex) JNK3MTL4
CATMyosin
CAPE
Sulfatetransporters
CD69
Chymase
CD8
PHT1
IFNgamma
EC-NOS
p65
CD25
Protein kinase D1
TLR4
TGFB1Pyrophosphatase
Radixpaeoniae
rubra
oxidases
Psoraleacorylifolia
Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease
Normal Model BFHX00
05
10
15
RL-m
ean
(cm
H2Omiddots
m)
lowastlowast lowastlowast
(a)Normal Model BFHX
00
05
10
15
20
25
lowast lowast
RL-m
ean
(cm
H2Omiddots
m)
(b)
Normal Model BFHX000
002
004
006
Cdy
n-m
ean
(mlc
mH
2O
)
lowastlowast
lowastlowast
(c)Normal Model BFHX
0
1
2
3
PEF
(mls
)
lowast lowastlowast
(d)
Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 7
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (400x) BFHX (400x) Model (400x)
(b)
Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x
46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)
47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)
5 Discussion
Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways
Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)
Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
8 Evidence-Based Complementary and Alternative Medicine
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal Model BFHX0
10
20
30
Mas
son
(per
area
)
lowastlowast lowastlowast
(b)
Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9
which may improve fibrosis and improve lung function(Figure 6)
TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)
HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend
inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)
KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 9
Normal (200x) BFHX (200x) Model (200x)
(a)
Normal (200x) BFHX (200x) Model (200x)
(b)
Normal Model BFHX0
10000
20000
30000
HM
GB1
IOD
lowastlowastlowastlowast
(c)Normal Model BFHX
0
10000
20000
30000
40000
KGF
IOD
lowast lowast
(d)
Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9
reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)
sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that
BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs
6 Conclusion
We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
10 Evidence-Based Complementary and Alternative Medicine
Normal Model BFHX0
5000
10000
15000
20000
25000
TNF-
훼(p
gm
l)
lowastlowast lowastlowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1훽
(pg
ml)
lowastlowast lowast
Normal Model BFHX0
500
1000
1500IL
-17
(pg
ml)
lowast lowast
Normal Model BFHX0
2000
4000
6000
8000
IL-1
0 (p
gm
l)
lowastlowast lowast
0
2000
4000
6000
8000
10000
IL-6
(pg
ml)
Normal Model BFHX
lowastlowast lowast
0
100
200
300
400
500
IL-4
(pg
ml)
Normal Model BFHX
lowastlowastlowast
Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6
Normal Model BFHX0
1
2
3
IL-8
lowastlowast lowastlowast
Normal Model BFHX00
01
02
03
04
05
IgA
lowastlowast lowastlowast
Normal Model BFHX0
20
40
60
80
sIgA
BA
L (n
gm
l)
lowastlowast lowastlowast
Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7
reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model
Competing Interests
All authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contributions
Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying
Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work
References
[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009
[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002
[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Evidence-Based Complementary and Alternative Medicine 11
[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011
[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002
[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011
[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010
[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010
[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010
[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009
[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007
[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011
[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013
[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013
[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011
[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009
[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014
[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013
[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012
[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006
[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014
[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014
[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016
[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005
[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012
[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012
[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004
[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987
[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014
[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014
[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003
[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005
[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006
[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008
[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
12 Evidence-Based Complementary and Alternative Medicine
[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007
[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005
[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010
[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015
[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997
[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Submit your manuscripts athttpswwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom