PATHOGENESIS OF ASTHMA

By,TEJA NAVEEN.B

Asthma is associated with a specific chronic inflammation of the mucosa of the lower airways.

PATHOLOGY

• The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of mucosal mast cells.

• A characteristic finding is thickening of the basement membrane due to subepithelial collagen deposition.

• In fatal asthma there will be thickened and edematous wall along with occlusion of lumen by mucus plug

• Mucous plug is formed by glycoproteins secreted from goblet cells and plasma proteins from leaky bronchial vessels.

• There is also vasodilation and angiogenesis.• Pathologic changes are found in all

airways,but do not extend to lung parenchyma.

INFLAMMATION• There is inflammation in the respiratory

mucosa from the trachea to terminal bronchioles, but with a predominance in bronchi.

• The specific pattern of airway inflammation is assosciated with airway hyperresponsiveness(AHR)

• This physiological abnormality is assosciated with variable airflow obstruction.

• Many inflammatory cells are know to be involved in asthma with no key cell that is predominant.

INFLAMMATORY CELLS

• MAST CELLS• MACROPHAGES AND DENDRITIC CELLS• EOSINOPHILS• NEUTROPHILS• T-LYMPHOCYTES

MAST CELLS: Are activated by allergens through an IgE-dependent mechanism.• Mast cells release several bronchoconstrictor

mediators like histamine,prostaglandin D2,and cysteinyl leukotrienses, but also several cytokines, chemokines,growth factors and neurotrophins.

NEUTROPHILS:Increased in airways and sputum during acute exacerbations and in the presence of smoking• Determinant of lack of response to CS treatment

Macrophages and dendritic cells:

• Macrophages initiate a type of inflammatory response via the release of certain cytokines.

• Dendritic cells are the major antigen presenting cells.

• Migrate to regional lymphnodes,interact with regulatory cells to stimulate TH₂ production.

Eosinophils: These infiltration is a characteristic feature of asthmatic airways.• These are linked to the development of AHR

through the release of basic protiens and oxygen derived free radicals.

T-LYMPHOCYTES• Prominent source of cytokines• Increased no of activated T cells(CD₄) in

airway• TH₁ - IL-12,IFN-ɣ• 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)

INFLAMMATORY MEDIATORS

• CHEMOKINES• CYTOKINES• LEUKOTRIENES • PROSTANOIDS• IgE• NITRIC OXIDE

CHEMOKINES:• Recruitment or chemotaxis of inflammatory cells• Additional signalling function• Attractive target for therapy

CYTOKINES:• Multiple cytokines regulate chronic inflammation of

asthma• The TH2 cytokines IL-4,IL-5 and IL-13 mediate allergic

reaction• TNF-α and IL-1β, amplify the inflammatory response• Thymic stromal lymphopoietin causes release of

chemokines that attract TH2 cells.

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

• 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 basement membrane

EXTRACELLULAR MATRIX

• Prominent structural feature in Asthma• Thickening of lamina reticularis • Denuded epithelium expose BM to airspace• Subepithelium 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

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 .

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

AIRWAY REMODELLING

• Inflammation- thickening of sub BM• Mucus hypersecretion (Gland hyperplasia)• Subepithelial fibrosis• Airway smooth muscle hypertrophy• Angiogenesis

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