Involvement of tumor necrosis factor‐α in development of hepatic injury in galactosamine‐sensitized mice

Intravenous injection of lipopolysaccharide and D‐galactosamine, at doses of 0.2 μg/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—α with polyvalent rabbit anti‐mouse tumor necrosis factor—α antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor—α 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—α, 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. These results suggest that endogenous tumor necrosis factor—α participates in the pathogenesis of lipopolysaccharide‐elicited hepatic injury, and that tumor necrosis factor plays a crucial role in the development of liver necrosis in galactosamine‐sensitized mice. (HEPATOLOGY 1990;12:1187–1191).