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Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice

1989; Elsevier BV; Volume: 38; Issue: 4 Linguagem: Inglês

10.1016/0006-2952(89)90208-6

1873-2968

Gisa Tiegs, Marc Wolter, Albrecht Wendel,

Sulfur Compounds in Biology

Intravenous injection of murine recombinant tumor necrosis factor α(TNF-α) to male NMRI albino mice in doses greater than 4 μgkg (specific activity 4 × 107Umg) resulted in a fulminant hepatitis when animals had been sensitized 1hr before by intraperitoneal administration of 700 mgkg galactosamine. Liver injury was assessed by measurement of serum transaminases as well as sorbitol dehydrogenase activity 8 hr after administration of TNF-α. Pretreatment with either galactosamine or 40 μgkg TNF-α alone did not cause hepatitis. Pretreatment of galactosamine/TNF-α-injured mice with 800 mgkg uridine or with 6 mgkg calmidazolium fully protected the animals, while administration of either verapamil or nifedipine (100mgkg, respectively) had no significant effect. The following inhibitors of generation or action of leukotriene D4, which were previously shown to block galactosamine/ endotoxin-induced hepatitis in mice, failed to protect against galactosamine/TNF-α-induced intoxication: 200 μgkg dexamethasone, 174 mgkg BW 755 C or 13 × 10mgkg FPL 55712. In addition, unlike in the galactosamine/endotoxin model no prevention was achieved by pretreatment of galactosamine/TNF-α-injured animals with the following substances blocking the development of an ischemia/reperfusion syndrome: 2 × 100 mgkg allopurinol, 3.3 × 104Ukg Superoxide dismutase, 1010Ukg catalase or 10μgkg iloprost. We conclude from our results that tumor necrosis factor α is likely to act as a final mediator of endotoxin action in a sequence of events which includes formation of leukotriene D4 and reactive oxygen species.