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| Clinicians have long known that asthma is not a single disease; it exists in many forms. Evidence: Disease risks from early environmental factors and susceptibility genes, subsequent disease induction and progression from inflammation, and response to therapeutic agents. What susceptibility genes are we talking about? Studies suggest a genetic basis for airway hyperresponsiveness, including linkage to chromosomes 5q and 11q. Asthma clearly does not result from a single genetic abnormality; rather it is a complex multigenic disease with a strong environmental contribution. For example, allergic potential to inhaled allergens (e.g., dust mites, mold spores, cat dander) is found more commonly in asthmatic children or asthmatic adults whose asthma began in childhood than in those with adult-onset asthma. Despite the explosion of information about asthma, the nature of its basic pathogenesis has not been established. Edema, epithelial cell desquamation, and inflammatory cell infiltration are found not only in autopsy studies of severe asthma cases but even in patients with very mild asthma. Reconstructive lesions, including goblet cell hyperplasia, subepithelial fibrosis, smooth muscle cell hyperplasia, and myofibroblast hyperplasia can lead to remodeling of the airway wall. Although many types of descriptive studies have revealed a composite picture of asthma, they have failed to identify a basic unifying defect of neural mechanisms, inflammatory cells (mast cells, macrophages, eosinophils, neutrophils, and lymphocytes), mediators (interleukins, leukotrienes, prostaglandins, and platelet-activating factor), and intrinsic abnormalities of the arachidonic acid pathway and smooth muscle cells. Immunology: How did the body help in the wrong way, aggravating asthmatic attacks? 1. The Th2 lymphocytes mediate allergic inflammation in atopic asthmatics by a cytokine profile that involves IL-4 (which directs B lymphocytes to synthesize IgE), IL-5 (which is essential for the maturation of eosinophils), and IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). 2. Eosinophils are often present in the airways of asthmatics (more commonly in allergic but also in nonallergic patients), and these cells produce mediators that can exert damaging effects on the airways. 3. Anticytokine studies suggest that lipid mediators are products of arachidonic acid metabolism. They have been implicated in the airway inflammation of asthma and have been the target of pharmacologic antagonism by antileukotriene agents. 4. Prostaglandins are generated by the cyclooxygenation of arachidonic acid, and leukotrienes are generated by the lipoxygenation of arachidonic acid. The proinflammatory prostaglandins (prostaglandin [PG]D2, PGF2, and TXB2) cause bronchoconstriction, whereas other prostaglandins are considered protective and elicit bronchodilation (PGE2and PGI2, or prostacyclin). 5. Leukotrienes C4, D4, and E4 compose the compound formerly known as slow-reacting substance of anaphylaxis, a potent stimulus of smooth muscle contraction and mucus secretion. 6. Ultimately, mediators lead to degranulation of effector or proinflammatory cells in the airways that release other mediators and oxidants, a common final pathway that leads to the chronic injury and inflammation noted in asthma. The story during an asthmatic attack! The pathogenesis: Inhaled allergens elicit TH2 response ↓ Favours IgE production and eosinophil recruitment ↓ Reexposure of allergens ↓ Stimulates degranulation of mast cells by antigen-induced-cross linking of IgE bound on mucosal cells ↓ Released of pre-formed mediators ↓ Bronchospasm, vasodilation, mucus production ↓ Late phase reaction Inflammation with recruitment of neutrophils and eosinophils ↓ Eosinophils cause epithelial damage of the airways Concept of Airway Remodeling: When asthma gets out of control!The relation between the several types of airway inflammation (early-phase and late-phase events) and the concept of airway remodeling remain a source of intense research. What is airway remodeling?? Persistent airflow obstruction despite aggressive anti-inflammatory therapies, including ICS and systemic corticosteroids.
references : David M. LangSerpil C. ErzurumMani Kavuru |
pathopysiology
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