Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice.
Intravenous injection of murine recombinant tumor necrosis factor alpha(TNF-alpha) to male NMRI albino mice in doses greater than 4 micrograms/kg (specific activity 4 x 10(7) U/mg) resulted in a fulminant hepatitis when animals had been sensitized 1 hr before by intraperitoneal administration of 700 mg/kg galactosamine. Liver injury was assessed by measurement of serum transaminases as well as sorbitol dehydrogenase activity 8 hr after administration of TNF-alpha. Pretreatment with either galactosamine or 40 micrograms/kg TNF-alpha alone did not cause hepatitis. Pretreatment of galactosamine/TNF-alpha-injured mice with 800 mg/kg uridine or with 6 mg/kg calmidazolium fully protected the animals, while administration of either verapamil or nifedipine (100 mg/kg, 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-alpha-induced intoxication: 200 micrograms/kg dexamethasone, 174 mg/kg BW 755 C or 13 x 10 mg/kg FPL 55712. In addition, unlike in the galactosamine/endotoxin model no prevention was achieved by pretreatment of galactosamine/TNF-alpha-injured animals with the following substances blocking the development of an ischemia/reperfusion syndrome: 2 x 100 mg/kg allopurinol, 3.3 x 10(4) U/kg superoxide dismutase, 10(6) U/kg catalase or 10 micrograms/kg iloprost. We conclude from our results that tumor necrosis factor alpha 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.
Tiegs
G
G
University of Konstanz, Faculty of Biology, Federal Republic of Germany.
Wolter
M
M
Wendel
A
A
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000503:physiopathology; D004537:Eicosanoic Acids / Q000502:physiology; D004731:Endotoxins / Q000633:toxicity; D011464:Epoprostenol / Q000494:pharmacology; D005688:Galactosamine / Q000633:toxicity; D016285:Iloprost; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009543:Nifedipine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014700:Verapamil / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D004537:Eicosanoic Acids; D004731:Endotoxins; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; C031938:calmidazolium; D000493:Allopurinol; D005688:Galactosamine; D014700:Verapamil; D011464:Epoprostenol; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D009543:Nifedipine; D016285:Iloprost