Do leukotrienes mediate bile acid-induced gastric mucosal injury?

Leukotrienes C4 and D4 are potent vasoconstrictors and have been proposed as mediators of the severe gastric mucosal injury caused by a variety of necrotizing agents. The purpose of this study was to investigate the role of leukotrienes on the less severe gastric mucosal injury caused by low concentrations of bile acid. Prior to injury with 5 mM acidified taurocholate (pH 1.2), rat stomachs were pretreated with either normal saline, leukotrienes C4 or D4 (10(-6), 10(-8), and 10(-9) M), or SKF-104353 (a leukotriene D4 receptor antagonist 10(-7) M). Injury was assessed by measuring net transmucosal hydrogen ion flux, luminal appearance of DNA, and histologic injury. Topical pretreatment with LTC4 and LTD4 significantly increased bile acid-induced luminal hydrogen ion loss and DNA accumulation in a dose-dependent manner. Leukotriene receptor blockade with SKF-104353 significantly decreased these parameters. Thus, both LTC4 and LTD4 exacerbate the gastric mucosal injury caused by the application of low concentrations of bile acid while leukotriene receptor blockade reduces this injury (corroborated by histologic injury analysis). This study suggests that leukotrienes may be mediators of bile acid-induced gastric mucosal injury.