Is there a role for leukotrienes as mediators of ethanol-induced gastric mucosal damage?

Abstract

The role of leukotriene (LT) C4 as a mediator of ethanol-induced gastric mucosal damage was investigated. Rats were pretreated with a number of compounds, including inhibitors of leukotriene biosynthesis [4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one (L651,392), 3-amino-[m-(trifluoromethyl)-phenyl]-2-pyrazoline hydrochloride (BW755c), and dexamethasone] and agents that have previously been shown to reduce ethanol-induced damage [prostaglandin E2, 2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16-methyl prostaglandin E1 (Rioprostil), FPL52694] prior to oral administration of absolute ethanol. Ethanol administration resulted in a fourfold increase in LTC4 synthesis. LTC4 synthesis could be reduced significantly by pretreatment with L651,392 or dexamethasone without altering the susceptibility of the gastric mucosa to ethanol-induced damage. LTC4 release from hemorrhagic tissue was not significantly increased above that from samples of nonhemorrhagic tissue from the same stomachs. Furthermore, changes in LTB4 synthesis paralleled the changes in LTC4 synthesis observed after ethanol administration. The effects of ethanol on gastric eicosanoid synthesis were further examined using an ex vivo gastric chamber preparation that allowed for application of ethanol to only one side of the stomach. Such treatment resulted in significant increases in LTC4 synthesis on both sides of the stomach (compared with controls), although the increase on the challenged side was significantly greater than that on the nonchallenged side. These studies, thus, confirm that ethanol can stimulate gastric leukotriene synthesis independent of the production of hemorrhagic damage. Inhibition of LTC4 synthesis does not confer protection to the mucosa, suggesting that LTC4 does not play an important role in the etiology of ethanol-induced gastric damage.