FIGURE 20–1 Conceptual model for the immunopathogenesis of asthma. Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On re-exposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene (LT) C4, and platelet-activating factor (PAF). These agents provoke contraction of airway smooth muscle, causing the immediate fall in forced expiratory volume in 1 second (FEV1). Re-exposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins (IL) 4 and 5, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late asthmatic response, indicated by a second fall in FEV1 3–6 hours after the exposure.
leukotriene receptor antagonists), or interfere with the action of inflammatory cytokines (anti-IL-5 and anti-IL-13 monoclonal antibodies). Other drugs that might be expected to be effective in all forms of asthma are those that relax airway smooth muscle (sympathomimetic agents, phosphodiesterase inhibitors) or inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonists, also described as anticholinergic agents).
Another approach to asthma treatment is aimed at reducing the level of bronchial responsiveness. Because increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented both by reducing exposure to the allergens that provoke inflammation and by prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids (ICS).
This therapy, once expected to be effective for all forms of asthma, is now recognized to be more effective for allergic than nonallergic asthma (see Future Directions of Asthma Therapy below).
The drugs most used for asthma management are adrenoceptor agonists or sympathomimetic agents (used as “relievers” or bronchodilators) and inhaled corticosteroids (used as “controllers” or anti-inflammatory agents). Their basic pharmacology is presented (such as oxidant, Goblet cell mucus
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IL-5 and IL-13 production in the airway epithelium and subepithelial mucosa
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