Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipid s, are proinflammatory mediators that play an important role in the pathoph ysiology of asthma. These mediators are among the most potent of bronchocon strictors and cause vasodilation, increased microvascular permeability, exu dation of macromolecules and edema. The cysteinyl leukotrienes also have po tent chemoattractant properties for eosinophils, causing an influx of eosin ophils into the airway mucosa., which, further fuels the inflammatory proce ss. In addition, the cysteinyl leukotrienes are potent secretagogues and re duce ciliary motility, which may hinder mucociliary clearance. Asthmatic pa tients demonstrate increased production of cysteinyl leukotrienes during na turally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast and pranlukast inhibit bronchoconstriction in asthmatic patient s undergoing allergen, exercise, cold air or aspirin challenge. They attenu ate the hallmarks of asthmatic inflammation, including eosinophilia in the airway mucosa and peripheral blood. Moreover, exhaled nitric oxide concentr ations, another correlate of airway inflammation, are decreased during mont elukast treatment in children. Cysteinyl leukotriene synthesis is not block ed by corticosteroid therapy. This important observation suggests that the leukotriene receptor antagonists represent a novel therapeutic approach, on e that may provide benefits that are additive with corticosteroid therapy. This supposition is supported by clinical observations that treatment with leukotriene receptor antagonists significantly improve asthma control when added to inhaled corticosteroid therapy. Moreover, the bronchodilator prope rties of the leukotriene receptor antagonists are additive with those of P agonists. These data provide strong support for the use of leukotriene rece ptor antagonists for treating asthma.