Asthma Pathogenesis

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Narissara Suratannon, MD.

Transcript of Asthma Pathogenesis

Page 1: Asthma Pathogenesis

Narissara Suratannon, MD.

Page 2: Asthma Pathogenesis

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

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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

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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

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Picture from Middleton

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Stephen Holgate.JACI 2007:120;1233-44

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Normal airway epithelium compared with mildly symptomatic atopic asthma

Picture from Middleton

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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

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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

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Plane of separation between

columnar and basal cells:

disruption of desmosomal linkages

Creola bodies: slough clumps of epithelial cells

Picture from Middleton

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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

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2008;122:689-93

Regan et al.JACI 2008;122:689-93

Filaggrin

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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

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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

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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

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Int Arch Allergy Immunol 1999;118:437–439

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Int Arch Allergy Immunol 1999;118:437–439

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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

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Asthmatic patients : repair by simple, stratified squamous epithelium or goblet cells

Picture from Middleton

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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

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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

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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

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J Immunol 2005;174:8183–90

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J Immunol 2005;174:8183–90

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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

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A Novel Cytokine : TSLP

Stephen T. Holgate.JACI 2007;120:1233-44

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The bronchial epithelium is highlighted as a key site for asthma pathogenesis

Stephen T. Holgate.JACI 2007;120:1233-44

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RBM

Picture from Middleton

Hyalinization and thickening of lamina reticularis

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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

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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

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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

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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

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ST Holgate. Clin Exp Allergy 2008;38:872-97

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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

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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

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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

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NEJM 2002;346:1699-705

Mucosal layers Submucosal layers

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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

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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

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Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 89

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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

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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

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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

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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

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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

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Heterogenity of asthma; according to BAL

Eosinophilic asthma Neutrophilic asthma Mixed inflammatory

asthma Paucigranulocytic

asthma

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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

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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

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Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7 ’th edition P.893-915

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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

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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

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