IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACH

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IMPACT OF ASTHMA AND IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACH ALLERGIC RHINITIS ON EACH Arzu Yorgancıoğlu Arzu Yorgancıoğlu

description

IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACH. Arzu Yorgancıoğlu. Epidemiologic Anatomic Physiologic Immunopathologic Therapeutic. EMBRYOLOGIC DEVELOPMENT. Begins during the 4th week of gestation and continues after birth Nasal placode and prominences ; Nose - PowerPoint PPT Presentation

Transcript of IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACH

Page 1: IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACH

IMPACT OF ASTHMA AND IMPACT OF ASTHMA AND ALLERGIC RHINITIS ON EACHALLERGIC RHINITIS ON EACH

Arzu YorgancıoğluArzu Yorgancıoğlu

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EpidemiologicEpidemiologic AnatomicAnatomic PhysiologicPhysiologic ImmunopathologiImmunopathologi

cc TherapeuticTherapeutic

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EMBRYOLOGIC DEVELOPMENTEMBRYOLOGIC DEVELOPMENT Begins during the 4th week of gestation Begins during the 4th week of gestation

and continues after birthand continues after birth Nasal placode and prominences ;Nasal placode and prominences ;

NoseNose

Laryngotracheal groove in the ventral wall Laryngotracheal groove in the ventral wall of primitive pharynxof primitive pharynx ;;

Larynx,trachea and bronchi Larynx,trachea and bronchi

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Bousquet J JACI 2004;113

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ANATOMYANATOMY

SIMILARITIESSIMILARITIES

Chronology in Chronology in embryologyembryology

Respiratory epitheliumRespiratory epithelium

DIFFERENCESDIFFERENCES

Subepithelial capillaries, Subepithelial capillaries, arterial system, arterial system, venous,cavernous venous,cavernous sinosoidssinosoids

Cartilage (nasal fossa-Cartilage (nasal fossa-bronchi)bronchi)

No muscle in nasal No muscle in nasal cavity, cavity,

Lower airways Lower airways

SMOOTH SMOOTH MUSCLEMUSCLE

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Bousquet J JACI 2004;113VASCULAR ENGORGEMENT BRONCHOCONSTRICTION

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Chronic Allergic Inflammatory Airway Chronic Allergic Inflammatory Airway SyndromeSyndrome

Allergic RhinitisAllergic Rhinitis

Allergic rhinitis + Bronchial Allergic rhinitis + Bronchial HyperreactivityHyperreactivity

Allergic Rhinitis + AsthmaAllergic Rhinitis + Asthma

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Vertical and Horizontal Vertical and Horizontal RelationshipRelationship

Togias A JACI 2003;111

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Togias A Allergy 1999;54(suppl 57):94..

Aspiration of Inflammatory Material

Oral breathing

Nasopharyngo-bronchial reflex

Systemic Propagation of Nasal Inflammation

VERTICAL RELATIONSHIPVERTICAL RELATIONSHIPVERTICAL RELATIONSHIPVERTICAL RELATIONSHIP

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ASPIRATION OF INFLAMMATORY ASPIRATION OF INFLAMMATORY MATERIALMATERIAL

First contact for inhaled allergens, contact First contact for inhaled allergens, contact with nasal secretions, allergenity and with nasal secretions, allergenity and biologic activity biologic activity

Insufficient invivo data,rabbit study + Insufficient invivo data,rabbit study + No deposition of nasal secretions in lung No deposition of nasal secretions in lung

(Tc99m enj)(Tc99m enj)

Bardin P J Allergy Clin Immunol 1990;86:82

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ORAL BREATHINGORAL BREATHING

Bypassing the nose Bypassing the nose

Deprivation of lower airways from Deprivation of lower airways from protective mechanisms (Nasal air protective mechanisms (Nasal air conditioning, humidifying, filteringconditioning, humidifying, filtering

Possible detrimental consequences Possible detrimental consequences

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Healthy Indıvıdual Healthy Indıvıdual

Nasal provocation with dry cold airNasal provocation with dry cold airbronchoconstructionbronchoconstruction

With oral breathing , warming , local With oral breathing , warming , local anesthesia or antikcholinergicanesthesia or antikcholinergic no no responseresponse

NAZOBRONCHIAL REFLEXNAZOBRONCHIAL REFLEX

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AR +, Asthma -AR +, Asthma -

Provocation with natural or metacholine , Provocation with natural or metacholine , histamin histamin BHR +BHR +

Sensorineural apparatus of the inflamed Sensorineural apparatus of the inflamed nose is upregulatednose is upregulated nasobronchial nasobronchial reflex is upregulated as well.reflex is upregulated as well.

Simons Clin Exp All Rev 2003;3

NAZOBRONCHIAL REFLEXNAZOBRONCHIAL REFLEX

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Nasal allergen provocation increases bronchial Nasal allergen provocation increases bronchial hyperresponsivenesshyperresponsiveness

Change in Change in PCPC2020 after nasal provocation after nasal provocation

Corren J et al J Allergy Clin Immunol 1992;89:611-618.

0800Baseline

3

2

0

Geometricmean PC20

(methacholine,

mg/ml)

Plasebo (n=10)Allergen (n=10)

1200Postchallenge

1600Postchallenge

**

***

Time

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Prevalance of Prevalance of BronBronchial hyperresponsivenesschial hyperresponsiveness

Patients with allergic rhinitis develops bronchial Patients with allergic rhinitis develops bronchial hyperresponsivess in polen seasonhyperresponsivess in polen season

Madonini E et al J Allergy Clin Immunol 1987;79:358-363..

60

50

40

30

20

10

0

% of patients

Off season Season

(n=27)

11

48

p<0.02

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BronBronchial hyperresponsivenesschial hyperresponsiveness

0

20

40

60

80

% s

ubje

cts

controlsseasonalrhinitis

perennialrhinitis

seasonal+ perennial

rhinitis

asthma

- 821 adult

- 20-44 y

- PC20 methacholine ≤4mg

non-asthmatic without wheeze

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Nasal mucosa of rhinitic patients with Nasal mucosa of rhinitic patients with asthma responds more vigorously to asthma responds more vigorously to nasal cold dry air than the ones nasal cold dry air than the ones without asthmawithout asthma

Nasal response to natural cat Nasal response to natural cat allergen exposure is greater with allergen exposure is greater with rhinitis and asthma than in patients rhinitis and asthma than in patients with rhinitis alonewith rhinitis alone

The presence of asthma and rhinitis The presence of asthma and rhinitis signifies a higher degree of signifies a higher degree of functional abnormality of the entire functional abnormality of the entire airwayairway

Hanes LS Clinical and Experimental Allergy 2006;36:26

Corren J J Allergy Clin Immunol 2005 ;

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BHR Asymptomatic in rhinitic BHR Asymptomatic in rhinitic patientspatients

Close connection between BHR and Close connection between BHR and allergen exposure allergen exposure

A relationship between the degree A relationship between the degree of BHRof BHR

And FEF 25-75 And FEF 25-75

Ciprandi G Respiratory medicine 2004;98:826

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SYSTEMIC SYSTEMIC INFLAMMATIONINFLAMMATION

CLINICAL CLINICAL

DATADATA

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Common Immunologıcal Common Immunologıcal mechanismmechanism

Common Immunologıcal Common Immunologıcal mechanismmechanism

Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21

Kay AB N Engl J Med 2001;344

IgE

Acute allergikreaction

Chronic allergikreaction

Mastcell

T cell

Allergen

Cytokines

Preformed mediatorsHistamine

Newly synthesized mediators

CysLT, PG, PAF

EosinophillsEosinophills

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Eosinophilic InfiltrationEosinophilic InfiltrationEosinophilic InfiltrationEosinophilic Infiltration

Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.

Eosinophil infiltration

Allergic rhinitis Astma

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Similarities in early and late Similarities in early and late responseresponse

Similarities in early and late Similarities in early and late responseresponse

Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172-1185

Togias A. J Allergy Clin Immunol 2000;105(6 pt 2):S599-S604.

AsthmaAllergic rhinitis

Symptom score

Time(h)

1Antigenprovocation

3–4 8–12 24

Early phase Late Phase

FEV1

(% change)

Time (h)

1 10 240 2 3 4 5 6 7 8 9

0

50

100

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NASAL PROVOCATION SYSTEMIC RESPONSE

Nasal allergen provocation Nasal allergen provocation peripheric peripheric eosinophiliaeosinophilia

Togias A J Allergy Clin Immunol 2000:106.Togias A J Allergy Clin Immunol 2000:106.

Nasal provocationNasal provocation spontaneus cytokine spontaneus cytokine decharge from peripheric leucocystsdecharge from peripheric leucocysts

Togias A J Allergy Clin Immunol 2002:109.Togias A J Allergy Clin Immunol 2002:109.

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0

100

200

300

400

500

600

700

Basal 24h after provocation

Eosi

noph

ils /

mm

3 P=0.004

Togias JACI 2000; 106: 247 - 50

NASAL PROVOCATION SYSTEMIC RESPONSE

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Increase in eosinophils in bronchial Increase in eosinophils in bronchial epithelium after allergen provocationepithelium after allergen provocation

Braunstahl, Am J Respir Crit Care Med 2000; 161:2051-57.

****

*

1600

1200

800

400

0

T24

T0 B C

+cell/mm2

BM

K13 b

ron

ch

ial su

bep

ith

eliu

m

A

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Increase in Eosinophils in Increase in Eosinophils in Bronchial EpitheliumBronchial Epithelium

Braunstahl, Am J Respir Crit Care Med 2000; 161:2051-57.

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9 AR , 9 controls ( nasal provocation)9 AR , 9 controls ( nasal provocation) Symptom scores, PFT, Peripheric Blood, nasal Symptom scores, PFT, Peripheric Blood, nasal

and bronchial biopsy and bronchial biopsy ½ ve 12h ; pulmonary and nasal symptom ½ ve 12h ; pulmonary and nasal symptom

scores, functions scores, functions 24h; 24h;

Peripheric eosinophil and IL-5 Peripheric eosinophil and IL-5

Nasal + bronchial eosinophil and IL-5 Nasal + bronchial eosinophil and IL-5

Endothelial adhesion molecules in Endothelial adhesion molecules in

Nasal and bronchial mucosa Nasal and bronchial mucosa

Braunstahl GJ J Allergy Clin Immunol 2001:107Braunstahl GJ J Allergy Clin Immunol 2001:107

NASAL PROVOCATION SYSTEMIC RESPONSE

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Braunstahl GJ JACI 2001:107.Braunstahl GJ JACI 2001:107.

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Systemic Inflammatory Response to Systemic Inflammatory Response to Allergen ProvocationAllergen Provocation

Systemic Inflammatory Response to Systemic Inflammatory Response to Allergen ProvocationAllergen Provocation

0

10

20

30

40

50

60

70

80

90

Rinit Kontrol Rhinitis Control Rhinitis control

Basal

24h after allergen

ICAM-1/CD31 VCAM-1/CD31 ELAM-1/CD31

%

Braunstahl GJ et al. JACI 2001; 107: 469-76

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Nasal biopsyNasal biopsy(ICAM-1,VCAM-1,E-Selectin,CD31(ICAM-1,VCAM-1,E-Selectin,CD31

Braunstahl GJ JACI 2001:107Braunstahl GJ JACI 2001:107

24s

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Bronchial biopsyBronchial biopsy(ICAM-1,VCAM-1,E-Selectin,CD31(ICAM-1,VCAM-1,E-Selectin,CD31

Braunstahl GJ JACI 2001:107Braunstahl GJ JACI 2001:107

24s

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Inhalation study with 99mTcInhalation study with 99mTc No deposition in lung after nasal No deposition in lung after nasal

expositionexposition

Corren J J Allergy Clin Immunol 1992:89Corren J J Allergy Clin Immunol 1992:89..

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Segmental bronchial provocation in Segmental bronchial provocation in AR patientsAR patients

Eosinophilia after 24 hEosinophilia after 24 h Nasal and bronchial mucosa ; Nasal and bronchial mucosa ;

eosinophiliaeosinophilia

IL-5 IL-5

eotaksin + cell eotaksin + cell Braunstahl AJRCCM 2000:161.Braunstahl AJRCCM 2000:161.

BRONCHIAL PROVOCATION SYSTEMIC RESPONSE

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Segmental bronchial provocation in AR Segmental bronchial provocation in AR 24 s; 24 s;

Nasal mucosal mast c.(degranulation) Nasal mucosal mast c.(degranulation) and basophil and basophil

Peripheric basophilia (migration) Peripheric basophilia (migration)

Lower and upper airways; eosinophil , IL Lower and upper airways; eosinophil , IL 5 and eotaksin positive cells5 and eotaksin positive cells

Braunstahl AJRCCM 2001:164.Braunstahl AJRCCM 2001:164.

BRONCHIAL PROVOCATION SYSTEMIC RESPONSE

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9 atopic asthmatics9 atopic asthmatics9 AR, Asthma –9 AR, Asthma –

Segmental bronchial provocationSegmental bronchial provocation

BAL; cell count, histamine, MMP, IL-5, BAL; cell count, histamine, MMP, IL-5, IFN- IFN- , IL-10 , IL-10

Cell,mediatör and cytokine profile Cell,mediatör and cytokine profile similarsimilar

PD causing airway response change 5 PD causing airway response change 5 times lower in asthmaticstimes lower in asthmatics

Preexisting airway sensitivity, injury, Preexisting airway sensitivity, injury, remodeling??remodeling??

Kelly E J Allergy Clin Immunol 2003;111:79.

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Nasal mucosal inflammation in Nasal mucosal inflammation in Asthma in the absence of Asthma in the absence of

rhinitisrhinitis

Nasal mucosal inflammation in Nasal mucosal inflammation in Asthma in the absence of Asthma in the absence of

rhinitisrhinitis

Gaga M et al Clin Exp Allergy 2000;20:663-669.

18

16

14

12

10

8

6

4

2

0

Eosinophils

Rhinitis No Rhinitis Control

(n=9) (n=8) (n=10)

p<0.001p<0.001

Asthma

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Eosinophils in asthmaticsEosinophils in asthmatics

Bousquet J et al. N Engl J Med 1990

Bronchial mucosa

Chanez P et al. Am J Respir Crit Care Med 1999

Nasal mucosa

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Similar airway findings in patients Similar airway findings in patients with rhinitis without asthmawith rhinitis without asthma

Bavbek S, J Invest Allergol Clin Immunol 1996; 6(3): 172-182

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RESULTRESULT

AR-Asthma relationship AR-Asthma relationship BIDIRECTIONALBIDIRECTIONAL

Local allergen exposure Local allergen exposure causes generalized causes generalized airway inflammationairway inflammation

SYSTEMIC RESPONSE SYSTEMIC RESPONSE due to IL-5 due to IL-5

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DIFFERENCESDIFFERENCES

Pathogenetic mechanisms and the Pathogenetic mechanisms and the resultant inflammation ; not differentresultant inflammation ; not different

Difference due to TARGET ORGAN Difference due to TARGET ORGAN characteristics (intrinsic features)characteristics (intrinsic features)

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Immunopathologic Immunopathologic Differences between Differences between Rhinitis and AsthmaRhinitis and Asthma

Epithelial injury – Specific for asthmaEpithelial injury – Specific for asthma

Remodelling – Specific for asthmaRemodelling – Specific for asthma

Mechanism in hyprereactivity - ?Mechanism in hyprereactivity - ? sensorineural in nose sensorineural in nose

Multifaceted in lung Multifaceted in lung

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Chanez P AJRCCM 1999;159Chanez P AJRCCM 1999;159

Nasal control Nasal patient

Bronchial kcntrol Bronchial patient

Epithelial Shedding

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EPITHELIAL SHEDDINGEPITHELIAL SHEDDING

Epithelial sheeding more prominent in Epithelial sheeding more prominent in bronchus (correlating with disease severity) bronchus (correlating with disease severity)

The less severe eosinophilic inflammation ?The less severe eosinophilic inflammation ?A reason other than eosinophils (Episialin ?)A reason other than eosinophils (Episialin ?)

Polosa R J Allergy Clin Immunol 2000;106:1124Shaida A J Allergy Clin Immunol 2001;108:791

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EPITHELIAL SHEDDINGEPITHELIAL SHEDDING

The characteristics of nasal mucosa The characteristics of nasal mucosa Higher clearance rateHigher clearance rate More resistance to injuryMore resistance to injury Higher regeneration capacityHigher regeneration capacity Protection against MMP Protection against MMP

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Basal Membrane in RhinitisBasal Membrane in Rhinitis Thickness of the nasal epithelium in patients with PAR Thickness of the nasal epithelium in patients with PAR

is greater than that of patients with SAR and controlsis greater than that of patients with SAR and controls

Calderon et al. JACI 1994; 93: 635-43

Thickness of BM is greater in Thickness of BM is greater in patients with SAR than controlspatients with SAR than controls

Lim et al. Am J Respir Crit Care Med 1995; 151: 136-44

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Thickness of Nasal and Bronchial Basal Thickness of Nasal and Bronchial Basal Membrane in Steroid -dependant Membrane in Steroid -dependant

asthmaticsasthmatics

Thickness of Nasal and Bronchial Basal Thickness of Nasal and Bronchial Basal Membrane in Steroid -dependant Membrane in Steroid -dependant

asthmaticsasthmatics

Chanez P et al. Am J Respir Cit Care Med 1999; 159: 588-95

Control Asthma

Basal membra

ne Thicknes

s(mm)

Nose Bronchus Nose Bronchus

14

12

10

8

6

4

2

0

14

12

10

8

6

4

2

0

p<0.004

p<0.001

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BM thickening more prominent in BM thickening more prominent in bronchusbronchus

Episialine (antiadhesion molecule Episialine (antiadhesion molecule secreted by epithelium)s ignificantly secreted by epithelium)s ignificantly more in bronchusmore in bronchus

Chanez P AJRCCM 1999;159Chanez P AJRCCM 1999;159

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Episialine immunoreactivityEpisialine immunoreactivity

Chanez P AJRCCM 1999;159Chanez P AJRCCM 1999;159

NASAL

BRONCHIAL

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Upper airway response leads to less Upper airway response leads to less remodeling??remodeling??

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REMODELLINGREMODELLINGNasal Nasal mucosamucosa

Bronchial Bronchial mucosamucosa

Epithelial Epithelial sheddingshedding

minimalminimal Often(Sp Often(Sp severe )severe )

BM ThickeningBM Thickening LimitedLimited OftenOften

EosinophilsEosinophils ++++ ++++++

CollagenCollagen (+-)(+-) ++++

FibroblastFibroblast May May invcreaseinvcrease

++++++

MyofibroblastMyofibroblast ?? ++++++

Smooth Smooth MuscleMuscle

-- Metaplasia, Metaplasia, hyperplasiahyperplasia

Bousquet J JACI 2004;113

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Another bronchial factor causing BM Another bronchial factor causing BM thickening???thickening???

Fibroblast? Myofibroblast?Fibroblast? Myofibroblast? Protease-antiprotease ?Protease-antiprotease ?

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SMOOTH MUSCLESMOOTH MUSCLE

Basic difference Basic difference Self interaction with epithelial , and Self interaction with epithelial , and

mezenchymal cellsmezenchymal cells Ep. Sheeding and thickening of BM is Ep. Sheeding and thickening of BM is

related with the secretory activity of related with the secretory activity of smooth muscle cellsmooth muscle cell

Effected by the cytokines releasedEffected by the cytokines released

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1.1. The secretory characteristics of The secretory characteristics of smooth muscle cellsmooth muscle cell

2.2. Genetic defects in embryologic Genetic defects in embryologic differentiation differentiation

Genes in the embryologic Genes in the embryologic differentiation may direct differentiation may direct remodeling ???remodeling ???

Emryologic origins are different Emryologic origins are different Bousquet J JACI 2004;113Salib RJ Clin Exp Allergy 2003:33

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RHINITISRHINITIS

Epithelial-Epithelial-mesenchymal mesenchymal trophic unittrophic unit

ASTHMAASTHMA Epithelial --Epithelial --

mesenchymanl-mesenchymanl-MUSCULAR trophic MUSCULAR trophic unitunit

Bousquet J et al J Allergy Clin Immunol Suppl 2001;108

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RESULTRESULT

Immunopathogenetic processses ; not Immunopathogenetic processses ; not differentdifferent

Different manifestations of the same Different manifestations of the same pathogenetic process in different parts of pathogenetic process in different parts of the airwaysthe airways

The difference in remodeling; due to The difference in remodeling; due to structural and intinsic characteristics of structural and intinsic characteristics of the Upper ve lower respiratory tracts the Upper ve lower respiratory tracts

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