Pathogenesis

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When challenged with the appropriate stimulus, the asthmatic patient experiences bronchial obstruction. Trigger events may be an identified allergen (pollen, grass, dust, food, hymenoptera venom, or drugs) or non-specific factors such as cold, smoke irritants, air pollution, viral infection, or emotional stress. Airway narrowing results from smooth muscle spasm, mucosal inflammation, and/or occlusion of bronchial lumen by thick mucus. Involvement of these three components varies, with exclusive or preponderant bronchospasm being able to achieve lumen obstruction. Postmortem examination and biopsies have revealed infiltration of bronchial submucosa by eosinophils and mast cells, local denudation of mucosa, deposition of dense collagen beneath basal membrane, proliferation and hyperplasia of goblet cells, smooth muscle hypertrophy, and airways plugged by thick mucus (Fig 1 and Fig, 2). These tenacious secretions contain mucus, inflammatory exudate with plasma proteins, epithelial cells, and inflammatory cells (mainly eosinophils). Expectorations with a large eosinophil content are known as Charcot-Leyden crystals. However, in some asthma deaths the only pathological findings are empty airways and predominant neutrophil infiltration of bronchial walls. Histamine, leukotrienes, prostaglandins, thromboxane, and other vasoactive and bronchoconstrictive substances have been recovered from asthmatic bronchoalveolar lavage, suggesting a complex effect of numerous immunological and inflammatory mediators.

Fig. 1 Mucus plugging a dilated bronchiole surrounded by inflammatory cells. (Reproduced with permission from Schaller, elal. „(1,996).)

Following allergen exposure, B lymphocytes synthesize immunoglobin E (IgE) which is bound to mast cell surfaces preferentially but not exclusively; it also binds with lower affinity to other cells (eosinophils, macrophages, platelets) ( Fig, 3). T lymphocytes play a major role in orchestrating immunoinflammatory response; mainly through the release of interleukins, they enhance IgE production by B lymphocytes, differentiate mast cells, and prime eosinophils. In the presence of allergens or other non-specific stimuli, mast cells degranulate and release histamine, prostaglandins, leukotrienes, and tryptase, thus promoting bronchoconstriction, dilatation of blood vessels, increased permeability, and edema. They also modify the viscosity of mucus and enhance its production. This is known as immediate or early allergic reaction. Eosinophils release vasoactive and bronchoconstritive substances as well as cytotoxic factors. Major basic protein, peroxidase, and neurotoxin damage surrounding tissues, leading to epithelial shedding. They also depress ciliary function and hence clearance of mucus from the airways. Under these conditions, the unprotected nerve endings are easily stimulated. The ensuing parasympathetic activation causes bronchoconstriction through acetylcholine release. These neuronal reflexes may also be initiated by psychological stress without an identified external trigger factor. Stimulation of non-myelinated C-fiber endings in the bronchial epithelium is responsible for a neuronal reflex with local neuropeptides release. Thus substance P promotes vascular permeability, mucus secretion, and bronchoconstriction, whereas neurokinin A causes bronchoconstriction. Other cells and mediators have been implicated in the development of bronchial obstruction: alveolar macrophages with release of superoxide radicals, chemotactic factors, thromboxane, leukotrienes and platelet activating factor (PAF), platelets with cytokines and platelet activating factor, damaged epithelial cells with decreased epithelial-derived bronchodilator factors, and lower mucosal protection.

Fig. 3 Schematic representation of cell-derived mediator effects: IL, interleukins; PG, prostaglandins; LT, leukotrienes; PAF, platelet activating factor.

These cellular, humoral, and neural mechanisms have all been implicated in the production of inflammation, edema, mucus accumulation, and muscle spasm. Autopsy findings following a prolonged and progressive asthma attack have confirmed extensive mucus plugging with marked airway inflammation. In addition, postmortem examinations of patients dying from a sudden asphyxic attack have shown empty airways and occasionally neutrophil infiltration, suggesting a predominant bronchospasm and distinct pathogenic mechanism in this setting.

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