Leukotrienes in the Pathogenesis of Asthma

¹ From the Asthma Research Group and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Asthma is a chronic inflammatory disease that is associated with widespread but variable airflow obstruction. The mechanisms that lead to airflow obstruction in asthma are bronchoconstriction, mucosal edema, increased secretion of mucus, and an inflammatory-cell infiltrate that is rich in eosinophils. Leukotrienes (LTs) B₄, C₄, D₄, and E₄ have been shown experimentally to play a role in each of these inflammatory mechanisms and to mimic the pathologic changes seen in asthma. Inhaled LTC₄ and LTD₄ are the most potent bronchoconstrictors yet studied in human subjects. LTC₄ and LTD₄ also may cause migration of inflammatory cells into the asthmatic airway. LTs are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, and increased production of LTs has been demonstrated in patients who have asthma. Leukotriene receptor antagonists and specific inhibitors of the 5-LO pathway hold great promise as new therapies to treat asthma. Because LTC₄, LTD₄, and LTE₄ appear to interact with a common LTD₄ receptor, selective LTD₄ receptor antagonists (eg, pranlukast [SB205312/ONO-1078], zafirlukast [ICI 204,219], MK-571, and MK-679), as well as zileuton (A-64077, a direct inhibitor of 5-LO) have been developed as antiasthma agents. Clinical and experimental studies have demonstrated the efficacy of these compounds in reducing not only the symptoms of asthma, but use of β₂-agonists and bronchoconstriction induced by exposure to allergens, exercise, aspirin, and cold air.

Key Words: allergen • asthma • bronchoconstriction • exercise • leukotriene • leukotriene receptor antagonist • 5-lipoxygenase • mediator