Asthma Pathogenesis
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Transcript of Asthma Pathogenesis
Narissara Suratannon, MD.
Topic included.. Pathology of asthma
Anatomical change Multicellular inflammation
Which are factors contributed to asthma pathogenesis (Filaggrin , TLSP, TARC,..?)
Distinct type of asthma : neutrophilic inflammation
Asthma A disorder of the conducting airways Through variety of provocation (different
pathways)…produce the same result of Airway hyperesponsiveness :
Contract too much, too easily spontaneously and in response to exogenous/endogenous stimuli
Variable airflow obstruction Multi-cellular inflammation
Stephen T. Holgate.Clin Exp Aller 2008:38;872-97
Pathology Epithelial desquamation Thickening of lamina reticularis Increased numbers of
myofibroblasts Evidence of airway remodeling
Hypertrophy and hyperplasia of airway smooth muscle
Mucous gland hyperplasia Angiogenesis
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Picture from Middleton
Stephen Holgate.JACI 2007:120;1233-44
Normal airway epithelium compared with mildly symptomatic atopic asthma
Picture from Middleton
The reason for that..
1. Fragility of epithelium
2. Defective of repairment
3. Tight junctions cannot fully developed
4. Loss of antioxidant function
5. Cytokines that damaged epithelium
Increase destruction : Fragility of epithelium
More severe in allergic than non-allergic forms Greater loss : greater degree of airway
responsiveness Reduced with glucocorticoid therapy Creola bodies
Epithelial cells from asthmatic airways, are unable to form effective TJs fully measurement of transepithelial resistance indicating increased leakiness
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Plane of separation between
columnar and basal cells:
disruption of desmosomal linkages
Creola bodies: slough clumps of epithelial cells
Picture from Middleton
Immunofluorescence with antibodies directed to ZO-1 and occludin confirmed poorly developed TJs in
asthmatic compared with normal cultures
Stephen Holgate.JACI 2007:120;1233-44
2008;122:689-93
Regan et al.JACI 2008;122:689-93
Filaggrin
At least in a subset of those with asthma, the filaggrin gene defect may be the fundamental predisposing factor not only for the development of eczema but also asthma
Tobacco smoke extract
Respiratory viruses
Proteolytically active allergens eg.Der p1
Oxidants (can break perijunctional actin)
Expose to Injurious agents & allergens: disrupted TJs
Stephen Holgate.JACI 2007:120;1233-44
Expose to Injurious agents & allergens: other mechanisms
Some chemical and biological agents insult tissue damaging through the generation of reactive oxygen species
Lack some of antioxidative capacity (Comhair SA et al.2007)
superoxide dismutase and glutathione peroxidase
Enhanced release of proinflammatory cytokines in response to diesel exhaust particle exposure
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Int Arch Allergy Immunol 1999;118:437–439
Int Arch Allergy Immunol 1999;118:437–439
Normal patients : mitotic activity in remaining epithelial cells by regeneration of normal ciliated and goblet cells : entired process 2 wks!
By stimulate intrinsic repair pathways with engagement of EGFRs by autocrine secretion of appropriate EGF family eg. EGF, heparin-binding EGF-like growth factor to drive cell migration, proliferation
Asthmatic epithelial cells : reduced expression of proliferative markers such as Ki67 (nuclear expression of cell cycle markers) and upregulation of cell cyclin inhibitor,nuclear p21wat
Defective repair of epithelium
Stephen Holgate.JACI 2007:120;1233-44
Asthmatic patients : repair by simple, stratified squamous epithelium or goblet cells
Picture from Middleton
Airway Epithelium As fragility and impaired proliferation; the epithelium
is chronically injuried and unable to repair properly
Leakiness of epithelium leading to greater access of inhaled allergens, pollutants and irritants
Consider asthma as a disease of impaired barrier function
Next assessment : gene regulation comparing asthmatic with normal epithelial cells
Stephen Holgate.Clin Exp Allergy 2008:38;872-97
Epithelial cells: as an effector cells Physiochemical barrier
Regulated recruitment, activation and differentiation of inflammatory cells in response to exogenous stimuli that cause epithelial damage from those cells remain Upregulated expression of ICAM-1 Proinflammatory cytokines (IL-1ß, TNF-α, IL-6) Cytokines (GM-CSF, G-CSF, IL-4, -13,-9, -5, -10, -11, -16,
TGFß) Peptide mediators – endothelin-1 and -3 (bronchoconstriction)
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
IL-8 (CXCL8) Potent chemoattractant of neutrophils
Eotaxin (CCL11) Chemoattractant of eosinophils = CCR3
RANTES (CCL5) Predominant chemoattractant of eosinophils
TARC (CCL17) Chemoattractant for Th2 lymphocytes = CCR4
J Immunol 2005;174:8183–90
J Immunol 2005;174:8183–90
Thymic stromal lymphopoietin is releasedby human epithelial cells in responseto microbes, trauma, or inflammation
and potently activates mast cells
Allakhverdi et al.JEM 2003:204(2);253–258
A Novel Cytokine : TSLP
Stephen T. Holgate.JACI 2007;120:1233-44
The bronchial epithelium is highlighted as a key site for asthma pathogenesis
Stephen T. Holgate.JACI 2007;120:1233-44
RBM
Picture from Middleton
Hyalinization and thickening of lamina reticularis
Basal membrane Initiated close to disease onset The extent of thickness does not relate to severity,
duration, fatality, responsiveness to control and does not progressive
Basal lamina (true basement membrane) Lamina reticularis/ reticular basement membrane
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Lamina Reticularis
Found only in humans and primates Reticulin fibers (collagen type I, III, VI), tenascin, heparin
sulfate and serum-derived components Homogenous hyaline in appearance Myofibroblast numbers beneath RBM correlating with
extent of collagen thickness Relate with epithelial secreting EGF familiy agents after
epithelial injury
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Smooth muscle Hyperplasia : larger airways (more characterized) Hypertrophy : smaller airways Cause from continuous irritation by mediators, repeated
episodes of bronchoconstriction, loss of inhibitory control with unopposed myogenic activity, EGF can induce airway smooth muscle mitogenesis
Correlate with fatal asthma more than long-standing process
Increase muscle mass : marked increase resistence to airway flow that may become life threatening
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Mucous secreting elements Submucosal gland enlargement and goblet cell
hyperplasia : histological hallmarks Numbers of goblet cells that secrete viscus mucus
increases, with a parallel reduction in cilated cells Goblet cells occurred in the more peripheral airways which
are normally devoid of goblet cells IL-4, IL-9, IL-13, TNF-α EGF play a significant role Mucus (adhere and continuity with goblet cell apex) mixed
with inflammatory exudative plugs in the airways in fatal asthma
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
ST Holgate. Clin Exp Allergy 2008;38:872-97
Cellular Infiltration Multicellular process :
Eosinophils (mainly) Neutrophils CD4+ T lymphocytes Mast cells : activated resident cells in airways Macrophages and dendrtitic cells : both resident
cells and recruitment to the lung NKT cells??
Recruited from circulation
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Mast cells Mucosal mast cells : Tryptase MCs Connective tissue mast cells : Chymase tryptase MCs
Histamine, PGD2, LTC4 : induce bronchoconstriction mucous secretion, mucosal edema
Cytokines (IL-4, IL-5, IL-13) : IgE synthesis, Th2 differentiation, eosinophilic inflammation
TNF-α, TGF-ß, FGF, tryptase, chymase - activated fibroblasts : airway remodelling
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Microlocalization of mast cells is a critical event in development of asthmatic phenotype
Airway smooth muscle TC mast cells infiltration in asthma, not in eosinophilic bronchitis : enhanced contractility
Also contributing to fibrogenesis and an increase in smooth muscle “remodelling response”
Mast cells
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
NEJM 2002;346:1699-705
Mucosal layers Submucosal layers
Interaction between mast cells and airway smooth muscle
SCF (c-kit ligand) : produced by epithelium, smooth muscle, fibroblasts
CXCL8/CXCL10 produced by airway smooth muscle interact with CXCR3/CXCR2 on mast cells (recruitment, enhanced mediator secretion)
Reverse reaction : mast cells secrete CCL19, stimulate airway smooth muscle through CCR7 stimulate muscle migration and contribute to smooth muscle hyperplasia
Stephen Holgate.Clin Exp Allergy 2008:38;872-97
Eosinophils• Very prominent cell
in allergic asthma
• IL-3, GM-CSF, eotaxin
: early derivation
• IL-5 : maturation and
recruitment into the
airways
Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 89
Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 89
Alveolar macrophages and dendritic cells
The most numerous cells in the airway lumen in normal and asthma patients
2 important roles Inflammatory cytokines
Proinflammatory cytokines :MIP-1α (CCL3), TNF-α, GM-CSF
Chemokines : CXCL8, CCL5, CCL11 Eicosanoids : prostaglandins, LTB4
Stephen Holgate.Clin Exp Allergy 2008:38;872-97
Anti-inflammatory cytokines : IL-10 Th1 cytokines : IL-12 Th2 cytokines : CCL17 and CCL22 in response to
allergen challenge
Role as APCs when interact with local inflammatory cytokines eg. TSLP : Th2 polarization
Alveolar macrophages and dendritic cells
Stephen Holgate.Clin Exp Allergy 2008:38;872-97
Lymphocytes Severity of asthma can be reflected by the activation
stage; CD25 Th2 cytokines :center role in secreting IL-4, IL-5, IL-13 Th1/Th2 imbalance should not be viewes as
pathognomonic for asthma Th1 shift does not lead to fewer asthma symptoms In severe asthma, we found elevation levels of IFN-Ɣ in
serum and BAL fluid Role of T-regulatory cells?? : little evidence
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Neutrophils Commonly found in airway of healthy patients Neutrophilic asthma During viral induced exacerbations
Role in asthma is still undefined Reflect of disease severity? A consequence of corticosteroid treatment
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Neutrophils mediate asthma pathogenesis through…
1. Potent proinflammatory functions : TNF-α, IL-1, IL-8, GM-CSF, G-CSF
2. Innate immune activation Epithelium of neutrophilic asthma express higher levels
of TLR2,4, CD 14 and surface protein A which may occur in response to increase in airway endotoxin, bacterial colonization and respiratory viruses
3. Role in airway remodeling via capacity of release TGF-ß, VEGF (in asthmatic patients)
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Heterogenity of asthma; according to BAL
Eosinophilic asthma Neutrophilic asthma Mixed inflammatory
asthma Paucigranulocytic
asthma
Neutrophillic asthma Patients who die sudden from asthma, severe asthma,
corticosteroid dependent
Tends to be older and a more aggressive disease with more tissue destruction and airway remodelling
Similar in terms of gender, atopy, smoking and lung function
Distinct immune and inflammatory mechanisms involving innate immune dysfunction
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Neutrophillic asthma
In response to involving pathogens; epithelial signals were sent to recruit inflammatory cells
If the responses are not insufficient to eliminate microbes; chronic persistent inflammation occurred and can damage host tissue
Evidence that innate immunity was stimulated Endotoxin levels esp. from H. influenza and
P. aeruginosa were increased
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915
Take Home Message Asthma is a heterogenous disease which has the
same manifestations of Airway hyperesponsiveness : Variable airflow obstruction Multi-cellular inflammation
Epithelium seems to be a key regulator of asthma Filaggrin gene polymorphisms have increased
risks of developing asthma in atopic eczema patients
Take Home Message Pathology
Epithelial disruption : Creola bodies Homogenous thickening of lamina reticularis Airway remodelling Mast cells infiltrated at airway smooth muscle
TARC and TSLP : Th2 polarization To know more about asthma pathogenesis could
contribute to know the target points of treatment