Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice

• Published in: Hepatology (Baltimore, Md.) Vol. 12; no. 5; p. 1187
• Main Authors: Hishinuma, I, Nagakawa, J, Hirota, K, Miyamoto, K, Tsukidate, K, Yamanaka, T, Katayama, K, Yamatsu, I
• Format: Journal Article
• Language: English
• Published: United States 01.11.1990
• Subjects: Alanine Transaminase - blood; Animals; Aspartate Aminotransferases - blood; Galactosamine - pharmacology; Immune Sera - immunology; Immunization, Passive; Lipopolysaccharides - pharmacology; Liver - drug effects; Liver - pathology; Mice; Mice, Inbred C3H; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.1840120518

Intravenous injection of lipopolysaccharide and D-galactosamine, at doses of 0.2 micrograms/kg and 800 mg/kg, respectively, elicited massive hepatic necrosis within 24 hr in C3H/HeN mice. The plasma L-alanine aminotransferase (ALT, E.C. 2.6.1.2) or L-aspartate aminotransferase (AST, E.C. 2.6.1.1) activities at this point reached more than 2,000 IU/L. However, overt hepatic injury as evaluated by the plasma aminotransferase activities did not develop in mice in which only lipopolysaccharide or only D-galactosamine was injected. No tumor necrosis factor-like activities could be detected in the plasma of galactosamine- and lipopolysaccharide-injected mice as determined by the assay of cytotoxicity to highly tumor necrosis factor-sensitive L-P3 cells through the experimental period of 24 hr. However, passive immunization against mouse tumor necrosis factor-alpha with polyvalent rabbit anti-mouse tumor necrosis factor-alpha antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor-alpha on L-P3 cells, could protect the mice from the development of hepatic injury in a dose-dependent manner. Simultaneous injection of recombinant human tumor necrosis factor-alpha, instead of lipopolysaccharide, with 800 mg/kg of D-galactosamine in lipopolysaccharide-resistant C3H/HeJ mice sensitized the animals more than one thousand-fold to the development of hepatic injury. The livers appeared to be morphologically similar to those of galactosamine- and lipopolysaccharide-injected C3H/HeN mice.