Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat
✍ Scribed by Y Iimuro; R M Gallucci; M I Luster; H Kono; R G Thurman
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 820 KB
- Volume
- 26
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
Tumor necrosis factor (TNF) a, a pivotal cytokine involved body may be therapeutically useful in this disease. (HEPATOL-OGY 1997;26:1530-1537.) in inflammation, is produced primarily by Kupffer cells in the liver. It has been shown that inactivation of Kupffer cells prevents alcohol-induced liver injury; therefore, the purpose It is well documented that liver disease can result from of this study was to determine if neutralizing anti-TNF-a dose-and time-dependent consumption of alcohol 1 ; howantibody is also effective. Male Wistar rats were exposed to ever, mechanisms remain unclear. With an enteral ethanol ethanol (11 to 12 grkg 01 rd 01 ) continuously for up to 4 weeks feeding model, 2,3 not only is steatosis observed, as is characvia intragastric feeding using an enteral feeding model. Before teristic of several models, 4 but inflammation and pericentral ethanol exposure, polyclonal anti-mouse TNF-a rabbit serum necrosis also occur within 4 weeks and fibrosis can be dewas injected (2.0 mg/kg intravenously). There were no signifitected within 6-8 weeks. Inactivation of Kupffer cells with cant differences in body weight, mean ethanol concentration, gadolinium chloride (GdCl 3 ) prevents early alcohol-induced or cyclic patterns of ethanol in urine when ethanol-and liver injury 5 and diminishes free radical formation in this ethanol plus antibody-treated groups were compared. Exmodel. 6 Moreover, intestinal sterilization with antibiotics pression of TNF-a and macrophage inflammatory protein 2
(polymixin B and neomycin) also prevents alcohol-induced (MIP-2) messenger RNA (mRNA), determined using reverse liver injury. 7 Taken together, these data support the hypothetranscription-polymerase chain reaction, was three-to foursis that activation of Kupffer cells by gut-derived endotoxin fold higher in livers of ethanol-treated rats than in those of is a primary event in the mechanism of alcohol-induced liver rats fed an ethanol-free, high-fat control diet. In addition, MIPinjury and that early alcoholic liver injury is dependent on 2 levels were also elevated when detected by Northern blot mild endotoxemia.
analysis. Anti-TNF-a antibody did not affect expression of
Activated Kupffer cells produce various mediators, includ-mRNA for interleukin (IL) 1a, IL-6, transforming growth facing cytokines, eicosanoids, proteases, and oxygen radicals, tor b 1 , or TNF-a. However, MIP-2 mRNA expression, which that participate in inflammation, immune responses, and is regulated by TNF-a, was decreased significantly by antimodulation of hepatocyte metabolism. 8 Plasma levels of tu-TNF-a antibody treatment. Serum aspartate transaminase levmor necrosis factor (TNF) a, 9,10 interleukin (IL) 1, 11 and ILels were elevated in ethanol-treated rats to 136 { 12 IU/L 6 12 were increased in patients with severe alcoholic hepatitis, after 4 weeks but only reached 90 { 5 IU/L (P õ .05) in rats and values corelated with the clinical course of the disease. 10 treated with anti-TNF-a antibody. The hepatic inflammation
Transforming growth factor (TGF) b is another critical cytoand necrosis observed in ethanol-fed rats were attenuated kine but is more important in fibrogenesis than inflammasignificantly by antibody treatment, and steatosis was not.
tion. 13 Increased levels of TGF-b were observed in superna-These results support the hypothesis that TNF-a plays an tants of isolated rat Kupffer cells after 10 weeks of treatment important role in inflammation and necrosis in alcohol-inwith ethanol and high-fat diet. 14 Moreover, in the Tsukaduced liver injury and that treatment with anti-TNF-a antimoto-French enteral feeding model, TNF-a messenger RNA (mRNA) expression increased in liver tissue after 4 weeks of treatment with ethanol.