The role of tumor necrosis factor-α in acute endotoxin-induced hepatotoxicity in ethanol-fed rats

Authors

  • John Hansen,

    1. Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417
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  • David L. Cherwitz,

    1. Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417
    Current affiliation:
    1. Genetics Program, Oregon State University, Corvallis, OR 97331
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  • John I. Allen M.D.

    Corresponding author
    1. Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417
    2. Virginia Piper Cancer Institute of Abbott Northwestern Hospital, Minneapolis, Minnesota 55407
    3. Digestive Healthcare Professional Association, Minneapolis, Minnesota 55404
    • Virginia Piper Cancer Institute, 800 E. 28th St., Minneapolis, MN 55407
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Abstract

An in vivo model of ethanol ingestion in rats was used to examine tumor necrosis factor-α production after intravenous injection with lipopolysaccharide or saline solution. Four groups of 125-gm male Sprague-Dawley rats were given one of the following four diets: liquid ethanol diet (ethanol, 36% of calories), liquid control diet, chow ad libitum or control liquid diet pair-fed to match calories consumed by ethanol-fed rats. After 6 wk of diet, all rats were injected with 1 mg/kg lipopolysaccharide or 0.9% saline. AST concentrations in the ethanol-lipopolysaccharide group (388 ± 54 U/ml) were significantly increased compared with those in control-saline, ethanol-saline and control-lipopolysaccharide groups (166 ± 23, 166 ± 18, 219 ± 47; p<0.01). Serum tumor necrosis factor-α concentrations for the ethanol-LPS group (3,990 ± 624 pg/ml) were increased compared with those in control-saline (87 ± 18), ethanol-saline (68 ± 24) and control-LPS (695 ± 165) groups (p<0.001). A strong correlation was seen between serum tumor necrosis factor-α and AST concentrations (r=0.91, p<0.001). Treatment with lipopolysaccharide also increased transcriptional levels of tumor necrosis factor-α-specific mRNA from hepatic Kupffer cells isolated from rats fed the long-term ethanol diet by a factor of 3 compared with control rats. From these data, we conclude that long-term ethanol administration sensitized hepatic Kupffer cells to secrete high levels of tumor necrosis factor-α after lipopolysaccharide injection. Increased serum tumor necrosis factor-α concentrations correlated directly with increased levels of serum transaminase, which may have reflected hepatic injury. (Hepatology 1994;20:461–474.)

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