Leukotriene-mediated liver injury

Abstract

The pathogenic mechanism of fulminant hepatitis induced by 700 mg/kg d-galactosamine plus 33 μg/kg endotoxin was investigated in male NMRI mice. The extent of liver injury was assessed by measurement of serum transaminases and sorbitol dehydrogenase activities 9hr after intoxication, as well as by histopathological evaluation. When the hepatic glutathione content of galactosamine endotoxin-treated animals had been decreased by more than 90% following administration of 250 mg/kg phorone or 400 mg/kg diethyl maleate given three times, no signs of liver injury were observed. Since different agents interfering with the leukotriene synthesis pathway also prevented galactosamine/ endotoxin-induced hepatitis, we suspected that a glutathione-derived peptidoleukotriene may be the pathogenic metabolite. In vivo inhibition of the catabolism of leukotriene C 4 by administration of 50 mg/kg of the glutamyi transpeptidase inhibitor AT 125 (Acivicin) also protected the animals against liver injury. In order to elucidate which metabolite of leukotriene C 4 was responsible for the observed hepatotoxicity we intravenously injected leukotrienes into animals that had received only galactosamine. Injection of 50 μg/kg leukotriene E 4 1hr after galactosamine had no effect. The same dose of leukotriene D 4 led to a fulminant hepatitis which was prevented when the leukotriene D 4 antagonist FPL 55 712 had been given before. In contrast, lipoxygenase inhibitors or AT 125 did not protect against galactosamine + LTD4. Galactosamine/endotoxin-induced and galactosamine/leukotriene D 4-induced hepatitis resulted in similarly localized histopathological changes, i.e. diffuse necrosis in the organ. We conclude from our results that galactosamine/endotoxin-induced hepatitis is mediated by a leukotriene D 4-dependent mechanism.