This work was supported by the Veterans Administration and National Institute on Alcohol Abuse and Alcoholism grant No. R01AA08237.
Tumor Necrosis Factor in Alcohol Enhanced Endotoxin Liver Injury
Article first published online: 11 APR 2006
Alcoholism: Clinical and Experimental Research
Volume 16, Issue 4, pages 665–669, August 1992
How to Cite
Honchel, R., Ray, M. B., Marsano, L., Cohen, D., Lee, E., Shedlofsky, S. and McClain, C. J. (1992), Tumor Necrosis Factor in Alcohol Enhanced Endotoxin Liver Injury. Alcoholism: Clinical and Experimental Research, 16: 665–669. doi: 10.1111/j.1530-0277.1992.tb00656.x
- Issue published online: 11 APR 2006
- Article first published online: 11 APR 2006
- Received for publication March 27, 1991; accepted January 23, 1992
- Tumor Necrosis Factor;
- Liver Injury
Endotoxin administration causes liver injury. Patients with alcoholic liver disease frequently have portal vein and systemic endotoxemia, and some investigators have suggested that endotoxin plays an etiologic role in alcoholic liver injury. Many of the metabolic effects of endotoxin are mediated by the cytokine tumor necrosis factor (TNF). It was the purpose of this study to determine whether TNF plays a role in ethanol-enhanced endotoxin liver injury. Rats were fed either a diet in which 36% of the calories were from ethanol or an isocaloric control diet. After 6 weeks, groups of 10 rats were intravenously injected with either saline, 1 mg/kg endotoxin, or 30 μg/kg of a prostaglandin E1 (PGE1) analogue + 1 mg/kg endotoxin 24 hr prior to sacrifice. Ethanol/endotoxin-treated rats had significantly higher liver enzyme levels (ALT 1064 ± 355 IU/liter, AST 2024 ± 515 IU/liter) compared with isocaloric/endotoxin controls (ALT 237 ± 54 IU/liter, AST 602 ± 80 IU/liter). Ethanol/endotoxin rats also had significantly higher peak serum TNF concentrations (992 ± 200 units/ml) compared with isocaloric/endotoxin controls (344 ± 96 units/ml). Pretreatment of ethanol/endotoxin rats with PGE1 caused significant attenuation of liver injury (ALT: 267 ± 64 IU/liter, AST 612 ± 77 IU/liter) and a diminished serum TNF response. In contrast to chronic ethanol administration, acute gavage with 2 mg/kg ethanol (30% w/v) followed by intravenous injection of 2 mg/ kg endotoxin produced significantly lower peak serum TNF concentrations (401 ± 76 units/ml) than gavage with distilled water (1152 ± 208 units/ml).
We conclude that chronic ethanol feeding enhances endotoxin-stimulated peak serum TNF concentrations, endotoxin liver injury, and pretreatment with the TNF synthesis inhibitor PGE1 attenuates this liver injury. Furthermore, acute and chronic alcohol feeding appear to have opposite effects on endotoxin stimulated serum TNF levels.