Overexpression of the leukotriene C4 synthase gene in mice reproduces human aspirin-induced asthma

Abstract

The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin /non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lopoxygenase (5-LO) metabolites, particularly leukotriene C4 (LTC4)&x3000;which is a highly potent bronchial constrictor. However, the role of LTC4 in the development of AIA has yet to be conclusively demonstrated. To elucidate the effect of LTC4 on the development of AIA, we generated LTC4 synthase (Ltc4s) gene transgenic (LTC4S-Tg) mice. In contrast to wild-type (WT) mice, LTC4S-Tg mice displayed NSAID-induced airway obstruction that was associated with increases of LTC4 and Th2 cytokines in lung tissue. This is the first study to demonstrate clearly that a balance shift towards the 5-LO pathway contributes to the pathogenesis of AIA in the presence of elevated levels of LTC4S.