Toxicological Sciences 56, 203-210 (2000)
Copyright © 2000 by the Society of Toxicology
Pentoxifylline Attenuates Bacterial Lipopolysaccharide-Induced Enhancement of Allyl Alcohol Hepatotoxicity
,1
* Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824; and
Institute for Environmental Toxicology and National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824
Small amounts of exogenous lipopolysaccharide (LPS) (10 ng/kg–100 µg/kg) enhance the hepatotoxicity of allyl alcohol in male Sprague-Dawley rats. This augmentation of allyl alcohol hepatotoxicity appears to be linked to Kupffer cell function, but the mechanism of Kupffer cell involvement is unknown. Since Kupffer cells produce tumor necrosis factor-alpha (TNF
) upon exposure to LPS, and this cytokine has been implicated in liver injury from large doses of LPS, we tested the hypothesis that TNF contributes to LPS enhancement of allyl alcohol hepatotoxicity. Rats were treated with LPS (10–100 µg/kg iv) 2 h before allyl alcohol (30 mg/kg ip). Co-treatment with LPS and allyl alcohol caused liver injury as assessed by an increase in activity of alanine aminotransferase in plasma. Treatment with LPS caused an increase in plasma TNF concentration, which was prevented by administration of either pentoxifylline (PTX) (100 mg/kg iv) or anti-TNF serum (1ml/rat iv) one h prior to LPS. Only PTX protected rats from LPS-induced enhancement of allyl alcohol hepatotoxicity; anti-TNF serum had no effect. Exposure of cultured hepatocytes to LPS (1–10 µg/ml) or to TNF (15–150 ng/ml) for 2 h did not increase the cytotoxicity of allyl alcohol (0.01–200 µM). These data suggest that neither LPS nor TNF alone was sufficient to increase the sensitivity of isolated hepatocytes to allyl alcohol. Furthermore, hepatocytes isolated from rats treated 2 h earlier with LPS (i.e., hepatocytes which were exposed in vivo to TNF and other inflammatory mediators) were no more sensitive to allyl alcohol-induced cytotoxicity than hepatocytes from naïve rats. These data suggest that circulating TNF is not involved in the mechanism by which LPS enhances hepatotoxicity of allyl alcohol and that the protective effect of PTX may be due to another of its biological effects.
Key Words: tumor necrosis factor-alpha (TNF); liver damage; Kupffer cells; allyl alcohol.
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