A model for allergic asthma. A, Sensitization to allergen. Inhaled allergens (antigens) elicit a TH2-dominated response favoringIgE production and eosinophil recruitment (priming or sensitization). B, Allergen-triggered asthma. On re-exposure to antigen (Ag) the immediate reaction is triggered by Ag-induced cross-linking of IgE bound to IgE receptors on mast cells in the airways. These cells release preformed mediators that open tight junctions between epithelial cells. Antigen can then enter the mucosa to activate mucosal mast cells and eosinophils, which in turn release additional mediators. Collectively, either directly or through neuronal reflexes, the mediators induce bronchospasm, increased vascular permeability, and mucus production, besides recruiting additional mediator-releasing cells from the blood. C, Late phase (hours). The arrival of recruited leukocytes (neutrophils, eosinophils, basophils, and TH2 cells) signals the initiation of the late phase of asthma and a fresh round of mediator release from leukocytes, endothelium, and epithelial cells. Factors, particularly from eosinophils (e.g., major basic protein, eosinophil cationic protein), also cause damage to the epithelium
Comparison of a normal bronchiole with that in a person with asthma. Note the accumulation of mucus in the bronchial lumen resulting from an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal mucous glands. In addition, there is intense chronic inflammation caused by recruitment of eosinophils, macrophages, TH2 cells and other inflammatory cells. Basement membrane underlying the mucosal epithelium is thickened, and there is hypertrophy and hyperplasia of smooth muscle cells
ASTHMAPATHOLOGY,PATHOGENESIS Dr.Amith Sreedharan DEPT OF PULMONARY MEDICINE SCB MCH , CUTTACK
DEFINITION• A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role.• The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing,breathlessness,chest tightness and coughing,particularly at night or in the early morning.• These episodes are usually associated with widespread but variable,airflow obstruction within the lung that is often reversible either spontaneously or with treatment
• 300 million affected individuals• 1% -18% - global prevalence• 15 million DALY – global burden
GENETICS Higher concordance in Monozygotic twins ↑ed incidence in primary relatives• ADAM-33 1st gene identified as Asthma susceptibility gene• 10 most common genes a/w Asthma Innate immunity (CD-14,HLA DRB1,DQB1) Th₂ cell signalling (IL-4,IL-13,IL-4Ra) Cellular inflammation (TNF,FCEDR1B) Lung development (ADAM33,ADRB2) GWAS : 17 q 21,11 p 14,5 q 23,Chr 18 Environment : Epigenetic modifications
ATOPIC ASTHMABegins in childhood.A positive family history of atopy is common,Asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema.The disease is triggered by environmental antigens, such as dusts, pollen, animal dander, and foods, but potentially any antigen is implicated.A skin test with the offending antigen results in an immediate wheal-and-flare reaction, a classic example of the type I IgE-mediated hypersensitivity reaction .
MODELS OF MECHANISMS OF ASTHMA• LATE PHASE ASTHMATIC RESPONSE MODELInhalation of allergenAcute phase response – immediate onsetWheezing,cough,SOBResolves within 1 hourLate phase response4-6 hours after allergen challengePersists for 24- 48 hoursIsolated LPR rare,seen in Occupational Asthma
• Late asthmatic reactions ̴ chronic asthma• Increased airway responsiveness• Decreased response to BD therapy• Bronchial inflammation• Asthma pts,with Dual phase: LPR prolonged and intense• Previously Airway Eosinophilia,now Basophil levels correlate with LPR• APR BAL:histamine,tryptase,PGD₂(mast cell)• LPR BAL :histame,tryptase no PGD₂(basophil)• Basophil: release Th₂ cytokines IL-4,IL-5,IL-13
Respiratory viruses and asthma• Respiratory syncitial virus,Rhino virus• Airaway hyperresponsiveness is increased• Persist as long as 4 weeks• Acute neutrophilic reponse• Potentiates eosinophilic airway inflammation• ↑ production of IL-8,GM-CSF,INFᵞ ,RANTES• Modulate airway environment,components of inflammation(cells and mediators)
NON ATOPIC ASTHMA• The mechanism of bronchial inflammation and hyper- responsiveness is much less clear in individuals with non-atopic asthma.• viral infections of the respiratory tract (most common) and inhaled air pollutants such as sulfur dioxide, ozone, and nitrogen dioxide.• In asthmatic subjects however, the bronchial response, manifested as spasm, is much more severe and sustained.• A positive family history is uncommon• serum IgE levels are normal• there are no associated allergies• virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants.• the ultimate humoral and cellular mediators of airway obstruction (e.g., eosinophils) are common to both atopic and non-atopic variants of asthma.
Sputum and BALCurschmann’s spiral• Cork screw shaped twists of condensed mucusCreola bodies• Clusters of surface airway epithelial cellsCharcot leyden crystals• Eosinophil cell and granule membrane lysophospholipase
• Airflow limitation in Asthma is recurrent and are caused by Bronchoconstriction IgE dependent mediators from Mast cells Airway edema Ìnflammation,mucus hypersecretion,mucus plugs,SM thickness Airway hyperresponsiveness Airway remodelling
Inflammatory cells in AsthmaEosinophilsMast cellsLymphocytesMonocytesNeutrophils
Eosinophils• Granulocytes derived from CD 34 cells• IL-5 development and terminal differentiation• Exposure to allergen,recruited into airway by chemotactic signals-chemokine EOTAXIN• Migration into airway dependant on extravasation of peripheral blood eosinophils• adhesion molecules on endothelium (VCAM 1) On eosinophils (VLA 4)• Recruitment of eosinophils IL-5,GM-CSF,RANTES• Upon entry into airway,release mediators granule proteins,leukotrienes(C₄),PG,cytokines.• Peripheral blood eosinophilia prominent feature of asthma
LYMPHOCYTES• Prominent source of cytokines• Increased no of activated T cells(CD₄) in airway• Th₁ - IL-12,IFN ᵞ• Th₂ - IL-4,IL-5,IL-9,IL-13• Th₂ predominant in asthma• IgE production (IL-4,IL-13)• Eosinophilia (IL-5)• Mucus secretion(IL-13)• Airway hyper responsiveness (IL-13)
MAST CELLS• Leukocytes that are effectors of inflammatory process• Immature form in peripheral circulation,differentiate upon localisation to a tissue compartment• Degranulation → inflammatory mediators• MC ̞ type- alveoli,bronchi & bronchioles• Tryptase : ↑ AR to histamine,stimulate fibroblast,↑collagen• Express high affinity IgE receptor & constitutively bound• Encountering Allergen,IgE molecules bind with allergen activates Mast cell• Immediate release of Histamine,tryptase,followed by LT,PG
Macrophage and Dendritic cells• Phagocytic cells capable of Antigen presenting• Critical role in clearing of microbes• Low affinity IgE receptors• Suppress inflammation by secretion of Th₁ cytokines(IL-12,IL-18,IFN ᵞ )• Dendritic cells- key antigen presenting cell• Migrate to regional LN,interact with regulatory cells to stimulate Th₂ production
NEUTROPHILS• Increased in airways and sputum during acute exacerbations and in the presence of smoking• Determinant of lack of response to CS treatment
Chemokines• Recruitment or chemotaxis of inflammatory cells• Additional signalling function• Attractive target for therapy• CCR5 inhibitor – currently in use
Cytokines involved in pathogenesis of asthmaIL-4• cross-linking of immunoglobulines in B lymphocytes – production of IgE and IgG4• increases of expression of VCAM-1 and mucous secretion• inhibits of activation of Th1 and production of IFNγ
IL-13• induces production of IgE a IgG4• activates mast cells• increases bronchial hyperreactivity and contractility of smooth muscles, affects the differentiation of cilia• induces the production of eotaxin, VCAM-1• supress production of pro-inflammatory cytokines
IL-5• produced by mast cells and Th2 lymphocytes, epithelial cells and eosinophils• affects the proliferation and the differentiation of B lymphocytes• induces expression of IL-2R• proliferating and differentiating factor for eosinophils
IL-12• produced by macrophages, dendritic cells and monocytes• decreases production of Th2 cytokines and then production of IgE and IgG1• decreases number of eosinophils in peripheral blood and in sputum
IL-10• large immunosupressive and anti- inflammatory effect• decreases expression of iNOS, COX2• decreases release of IL-2, expression of MHC class II., CD80, CD86 and CD32 on the surface of APC and then presentation of allergen, RANTES, IL-5• correlation with asthma severity
IFNγ• low levels in atopic people• stimulatory effects on Th1 cells, inhibitory effects on Th2 cells• the nebulissation of IFNγ decreases the number of eosinophils in BAL but this effect is not significant
TGF-β• remodeling• induction of expression of Fas receptor on the surface of epithelial cells, activation of apoptosis, fagocytosis by macrophages, exsudation of plasma, fibrosis
IgE• Allergic inflammation prominent role in asthma• Mast cell mediators –major role in Asthma• IgE – Mast cell activation• As target for therapy• Omalizumab
Leukotrienes• Arachidonic acid metabolites• Rapidly synthesised within minutes,following activation• LT C4,D4,E4 potent bronchoconstrictors• Produced by several cell types including eosinophils,mast cells• Also increase mucus secretion• Facilitate plasma leak,generating airway edema
PROSTANOIDS• Arachidonic acid metabolites via COX pathway• PGD₂,PGF₂,TXA₂ potent bronchoconstrictors• Produced by eosinophils,mast cells• PGD₂ predominant prostanoid involved.
NITRIC OXIDE• Role unclear• Low levels,a bronchodilator & vasodilator• Higher levels of NO in asthma• NO react with superoxide anion in inflamed tissue to produce biologic oxidants• Level of severity of airway inflammation• Exhaled NO tool to reflect airway inflammation
AIRWAY EPITHELIUM is central to pathogenesis of ASTHMA• Epithelial stimulation to epithelial shedding,even extensive areas of denudation• MBP ,EPO & ECP implicated in injury• Injured & stimulated epithelial cells secrete GM-CSF,IL-1,IL-8,RANTES.• Significant denudation of epithelium itself result in variety of secondary effects
• Loss of barrier function permit direct access of allergens on tissue cells (eg; mast cells)• Loss of epithelial cells reduces ability to degrade peptide and kinin mediators and to secrete EDRF(which maintain dilatation)• Sensory nerve exposure promote inflammation and bronchoconstriction• Provoke proliferation of myofibroblasts,secretion of extracellular matrix protein(collagen) leading to thickened BM
EXTRACELLULAR MATRIX• Prominent structural feature in Asthma• Thickening of lamina reticularis• Denuded epithelium expose BM to airspace• Sub BM is enlarged and dense by deposition of collagen,fibronectin,laminin….• Epithelial cells and myofibroblasts contribute to thickening• GF:TGF B,PDGF,FGF,endothelin
FIBROBLASTS AND MYOFIBROBLASTS• Abnormal mesenchymal cell proliferation & no of Fibroblasts,Myofibroblasts ↑ed.• MFB- tissue remodelling by releasing ECM components elastin,fibronectin,laminin.• Allergen challenge ↑no of MFB• Role : contractile response,mitogenesis,synthetic and secretory.• Release RANTES
SMOOTH MUSCLE CELLS• Excess accumulation of bronchial smooth muscle cells prominent feature of airway wall remodeling• pro-activating signals for converting airway smooth muscle cells into a proliferative and secretory cell in asthma are unknown, but may include viruses and IgE• Another mechanism regulating smooth muscle proliferation is through production of metalloproteinase (MMP)-2• nonspecific BHR is a basic mechanism underlying the excessive smooth muscle contraction and airway narrowing
NONSPECIFIC BHR• Major functional abnormality in asthma• Related to severity of symptoms over long periods• Response to wide range of stimuli• Not completely related to bronchial eosinophilic inflammation• Easier access of stimulus to epithelial & submucosal sites enhance BHR• Loss of epithelial tight junctions α BHR• Lamina reticularis thickness α BHR• More prolonged exposure leads to fibronectin,collagen deposition in the outer airway wall
NERVES• Dysfunction of the airway innervation in asthma contributes to its pathophysiology.• β-Adrenergic blockers and cholinergic agonists are known to induce bronchoconstriction and produce symptoms of asthma.• Nonadrenergic noncholinergic (NANC) neural pathways involving new neuromediators, such as bradykinin, neurokinin, vasoactive intestinal peptide (VIP), and substance P.• These neuromediators produce in vitro and in vivo features of clinical asthma involving bronchoconstriction, vasodilation, and inflammation.• The NANC system has been proposed as an explanation for bronchial hyperreactivity .• ↓ VIP secreting neurons
BLOOD VESSELS• Airway wall remodeling in asthma involves a number of changes including increased vascularity, vasodilation, and microvascular leakage.• number and size of bronchial vessels is moderately increased.• neovascularization or angiogenesis is still unclear.• Vascular endothelial growth factor (VEGF) levels are variable in asthmatic airways suggesting a low degree of angiogenesis in patients with controlled asthma.
GLANDS• Bronchial hypersecretion is the consequence of hypertrophy and hyperplasia of submucosal glands and epithelial goblet cells.• Increased mucus will certainly result in sputum production and contribute to excessive airway narrowing.• The replacement of ciliated cells by goblet cells contributes to airway remodeling in asthma.• Impaired clearance of mucus is present during exacerbations and is a potential important contributor to fatal asthma.
AIRWAY HYPERRESPONSIVENESS• Increased smooth muscle sensitivity and contracture• Dysfunctional neuroregulation• Increased maximal contraction of bronchial muscle as consequence of reduction/uncoupling of opposing forces (elastic recoil) Airway wall edema result in functional detachment of alveolar walls• Thickening of airway wall due to chronic inflammation ,result in increased resistance to airflow
SUMMARY• Asthma is characterized by reversible bronchoconstriction caused by airway hyper-responsiveness to a variety of stimuli.• Atopic asthma is caused by a TH2 and IgE-mediated immunologic reaction to environmental allergens and is characterized by acute (immediate) and late-phase reactions. The TH2 cytokines IL-4, IL-5, and IL-13 are important mediators.• Triggers for non-atopic asthma are less clear but include viral infections and inhaled air pollutants.• Eosinophils are key inflammatory cells found in all subtypes of asthma; eosinophil products such as major basic protein are responsible for airway damage.• Airway remodeling (basement membrane thickening and hypertrophy of bronchial smooth muscle) adds to the element of obstructive disease.