Asthma Pathogenesis
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    Asthma Pathogenesis Asthma Pathogenesis Presentation Transcript

    • 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: Creola bodies: slough disruption of desmosomal linkages 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
    • Filaggrin 2008;122: 689-93 Regan et al.JACI 2008;122:689-93
    • 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
    • Expose to Injurious agents & allergens: disrupted TJs Tobacco smoke extract Respiratory viruses Proteolytically active allergens eg.Der p1 Oxidants (can break perijunctional actin) 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
    • Defective repair of epithelium  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 Stephen Holgate.JACI 2007:120;1233-44
    • Asthmatic patients : repair by simple, stratified squamous epithelium or goblet cells
    • 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
    • Chemokines  CXC or α Chemokines  ELR (Glu-Leu-Arg) containing CXC : predominantly chemoattractant for neutrophils  Non-ELR CXC : induced by IFN  CC or ß chemokines : chemoattractants for eosinophils, basophils, monocytes, dendritic cells, lymphocytes
    • 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
    • A Novel Cytokine : TSLP  TSLP : IL-7 like cytokine  Correlations between TSLP expression, TARC/ CCL17,MDC/CCL22  Th2-polarization is more closely under the control of TSLP at the epithelium where the airways inter act with the environment  Altered responses to this interaction in asthmatics may reflect inherent abnormalities of the epithelium itself, such as altered responses to vira l infection Ying et al.J Immunol 2005;174:8183–90
    • The bronchial epithelium is highlighted as a key site for asthma pathogenesis Stephen T. Holgate. JACI 2007;120:1233-44
    • Hyalinization and thickening of lamina reticularis RBM Picture from Middleton
    • 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 Recruited from circulation  CD4+ T lymphocytes  Mast cells : activated resident cells in airways  Macrophages and dendrtitic cells : both resident cells and recruitment to the lung  NKT cells?? 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
    • Mast cells  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” Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
    • Mucosal layers Submucosal layers NEJM 2002;346:1699-705
    • 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 – 8
    • 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
    • Alveolar macrophages and dendritic cells  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 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