The role of tumor necrosis factor-alpha in acute endotoxin-induced hepatotoxicity in ethanol-fed rats.
An in vivo model of ethanol ingestion in rats was used to examine tumor necrosis factor-alpha 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-alpha 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-alpha and AST concentrations (r = 0.91, p < 0.001). Treatment with lipopolysaccharide also increased transcriptional levels of tumor necrosis factor-alpha-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-alpha after lipopolysaccharide injection. Increased serum tumor necrosis factor-alpha concentrations correlated directly with increased levels of serum transaminase, which may have reflected hepatic injury.
Hansen
J
J
Minneapolis Veterans Affairs Medical Center, Minnesota 55417.
Cherwitz
D L
DL
Allen
J I
JI
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015152:Blotting, Northern; D004731:Endotoxins / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000633:toxicity*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase