LIPOPOLYSACCHARIDE-NEUTRALIZING ANTIBODY REDUCES HEPATOCYTE INJURY FROM ACUTE HEPATOTOXIN ADMINISTRATION

Endogenous lipopolysaccharide has been implicated as a cofactor in the hepatocellular injury and death resulting from toxic liver injury. To prevent this lipopolysaccharide-induced injury and to further underst and the mechanism of this effect, an antilipopolysaccharide antibody w as administered to rats in which toxic hepatocellular injury was induc ed. Rats were given the hepatotoxin galactosamine together with an iso typic control antibody B55 or the antilipopolysaccharide antibody E5. E5 treatment resulted in reductions of serum AST levels of 43% at 36 h r (p < 0.02) and 60% at 48 hr (NS) after galactosamine administration. These decreases in AST values were accompanied by diminished histolog ical evidence of injury and inflammation. In carbon tetrachloride-indu ced liver injury, E5 similarly reduced serum AST levels at 36 and 48 h r by 47% (p < 0.04) and 54% (p < 0.03), respectively. E5 treatment was equally effective in reducing AST levels 48 hr after administration o f carbon tetrachloride, whether the initial dose of antibody was given 1 hr before or 3 or 6 hr after the administration of this toxin. To u nderstand the mechanism of this E5 effect, the activation of the toxic cytokine tumor necrosis factor-or and the chemotactic cytokine monocy te chemoattractant protein 1 was examined by Northern-blot analysis of RNA from rat livers after galactosamine-induced injury and treatment with B55 or E5. Despite E5's efficacy in reducing hepatocellular damag e, E5 treatment did not affect the timing or magnitude of tumor necros is factor-or or monocyte chemoattractant protein 1 activation during g alactosamine-induced injury. These data suggest that antibody neutrali zation of lipopolysaccharide may be an effective therapy for toxic liv er injury and that the mechanism of this effect is not through the pre vention of cytokine expression.