Role of leukotrienes in asthma pathophysiology

Inflammation is an essential component of asthma pathophysiology. While beta(2)-agonists are often used for short-term relief of acute bronchospasm, anti-inflammatory agents are required for the long-term management of chronic inflammation in this disease. Corticosteroids have emerged as the first-line anti-inflammatory therapy for asthma management. However, in some patients, especially children, the high doses of corticosteroids that may be required to control features of hyperresponsiveness, including exercise-induced asthma, raise safety concerns. Thus, there is a need for complementary anti-inflammatory, steroid-sparing agents in asthma therapy. Several inflammatory mediators have been targeted in an attempt to thwart this inflammatory process, but so far with little success. The cysteinyl leukotrienes (CysLT), LTC(4), LTD(4), and LTE(4), have been shown to be essential mediators in asthma, making them obvious targets for therapy. These cysteinyl leukotrienes, previously known as the slow-reacting substance of anaphylaxis (SRS-A), mediate many of the features of asthma, including bronchial constriction, bronchial hyperreactivity, edema, and eosinophilia. Data show that selective cysteinyl leukotriene receptor antagonists (CysLTRAs) effectively reverse these pathologic changes. Corticosteroids do not inhibit the production of CysLTs in vivo, suggesting that CysLTRAs and corticosteroids affect different targets. The bronchodilator properties of CysLTRAs seem to be additive to those of beta(2)-agonists and corticosteroids. These data suggest that CysLTs are important therapeutic targets in the management of inflammation in asthma.