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INTRODUCTION

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  • Asthma, as defined by the Global Initiative for Asthma (GINA), is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation.

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PATHOPHYSIOLOGY

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  • There is a variable degree of airflow obstruction (related to bronchospasm, edema, and hypersecretion), bronchial hyperresponsiveness (BHR), and airway inflammation.

  • In acute inflammation, inhaled allergens in allergic patients causes early-phase allergic reaction with activation of cells bearing allergen-specific immunoglobulin E (IgE) antibodies. After rapid activation, airway mast cells and macrophages release proinflammatory mediators such as histamine and eicosanoids that induce contraction of airway smooth muscle, mucus secretion, vasodilation, and exudation of plasma in the airways. Plasma protein leakage induces a thickened, engorged, edematous airway wall and narrowing of lumen with reduced mucus clearance.

  • Late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation and involves recruitment and activation of eosinophils, T lymphocytes, basophils, neutrophils, and macrophages. Eosinophils migrate to airways and release inflammatory mediators.

  • T-lymphocyte activation leads to release of cytokines from type 2 T-helper (TH2) cells that mediate allergic inflammation (interleukin [IL]-4, IL-5, and IL-13). Conversely, type 1 T-helper (TH1) cells produce IL-2 and interferon-γ that are essential for cellular defense mechanisms. Allergic asthmatic inflammation may result from imbalance between TH1 and TH2 cells.

  • Mast cell degranulation results in release of mediators such as histamine; eosinophil and neutrophil chemotactic factors; leukotrienes C4, D4, and E4; prostaglandins; and platelet-activating factor (PAF). Histamine can induce smooth muscle constriction and bronchospasm and may contribute to mucosal edema and mucus secretion.

  • Alveolar macrophages release inflammatory mediators, including proinflammatory and anti-inflammatory cytokines, reactive oxygen species, and eicosanoids. Production of neutrophil chemotactic factor and eosinophil chemotactic factor furthers the inflammatory process. Neutrophils also release mediators (PAFs, prostaglandins, thromboxanes, and leukotrienes) that contribute to BHR and airway inflammation. Leukotrienes C4, D4, and E4 are released during inflammatory processes in the lung and produce bronchospasm, mucus secretion, microvascular permeability, and airway edema.

  • Bronchial epithelial cells participate in inflammation by releasing eicosanoids, peptidases, matrix proteins, cytokines, and nitric oxide. Epithelial shedding results in heightened airway responsiveness, altered permeability of airway mucosa, depletion of epithelial-derived relaxant factors, and loss of enzymes responsible for degrading inflammatory neuropeptides. The exudative inflammatory process and sloughing of epithelial cells into the airway lumen impair mucociliary transport. Bronchial glands increase in size, and goblet cells increase in size and number.

  • The airway is innervated by parasympathetic, sympathetic, and nonadrenergic inhibitory nerves. Normal resting tone of airway smooth muscle is maintained by vagal efferent activity, and bronchoconstriction can be mediated by vagal stimulation in small bronchi. Airway smooth muscle contains noninnervated β2-adrenergic receptors that produce bronchodilation. The nonadrenergic, noncholinergic nervous system in the trachea and ...

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