Pentoxifylline attenuates bacterial lipopolysaccharide-induced enhancementof allyl alcohol hepatotoxicity

Small amounts of exogenous lipopolysaccharide (LPS) (10 ng/kg-100 mu g/kg) enhance the hepatotoxicity of allyl alcohol in male Sprague-Dawley rats. Th is augmentation of allyl alcohol hepatotoxicity appears to be linked to Kup ffer cell function, but the mechanism of Kupffer cell involvement is unknow n. Since Kupffer cells produce tumor necrosis factor-alpha (TNF alpha) upon exposure to LPS, and this cytokine has been implicated in liver injury fro m large doses of LPS, we tested the hypothesis that TNF alpha contributes t o LPS enhancement of allyl alcohol hepatotoxicity. Rats were treated with L PS (10-100 mu g/kg iv) 2 h before allyl alcohol (30 mg/kg ip). Go-treatment with LPS and allyl alcohol caused liver injury as assessed by an increase in activity of alanine aminotransferase in plasma. Treatment with LPS cause d an increase in plasma TNF alpha concentration, which was prevented by adm inistration of either pentoxifylline (PTX) (100 mg/kg iv) or anti-TNF alpha serum (1ml/rat iv) one h prior to LPS. Only PTX protected rats from LPS-in duced enhancement of allyl alcohol hepatotoxicity; anti-TNF alpha serum had no effect. Exposure of cultured hepatocytes to LPS (1-10 mu g/ml) or to TN F alpha (15-150 ng/ml) for 2 h did not increase the cytotoxicity of allyl a lcohol (0.01-200 mu M). These data suggest that neither LPS nor TNF alpha a lone was sufficient to increase the sensitivity of isolated hepatocytes to allyl alcohol. Furthermore, hepatocytes isolated from rats treated 2 h earl ier with LPS (i.e., hepatocytes which were exposed in vivo to TNF alpha and other inflammatory mediators) were no more sensitive to allyl alcohol-indu ced cytotoxicity than hepatocytes from naive rats. These data suggest that circulating TNF alpha is not involved in the mechanism by which LPS enhance s hepatotoxicity of allyl alcohol and that the protective effect of PTX may be due to another of its biological effects.