Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice.
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.
Hishinuma
I
I
Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki, Japan.
Nagakawa
J
J
Hirota
K
K
Miyamoto
K
K
Tsukidate
K
K
Yamanaka
T
T
Katayama
K
K
Yamatsu
I
I
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D005688:Galactosamine / Q000494:pharmacology*; D007106:Immune Sera / Q000276:immunology; D007116:Immunization, Passive; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D007106:Immune Sera; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase