ETHANOL FEEDING ENHANCES INFLAMMATORY CYTOKINE EXPRESSION IN LIPOPOLYSACCHARIDE-INDUCED HEPATITIS

Elevated concentrations of plasma tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 have been detected in patients with alcoho lic hepatitis and have been implicated in the pathogenesis of hepatocy te necrosis. The present study used a rat model to conduct a detailed histological and biochemical examination of the expression of various pro-inflammatory cytokines and associated liver pathology in ethanol-p otentiated lipopolysaccharide (LPS)-induced liver injury. Male Wistar rats were pair-fed either the control or ethanol-containing (36% of ca loric intake as ethanol) form of the Lieber-DeCarli liquid diet for 6 weeks. Liver injury was induced by the i.v. injection of LPS (1 mu g/g bodyweight), with animals being killed at O, 1, 3, 6, 12 and 24 h aft er injection. At the later time points, plasma transaminase and transp eptidase activities were significantly elevated in ethanol-fed LPS-tre ated rats compared with control-fed LPS-treated animals. At these time s after LPS treatment, hepatocytes in ethanol-fed animals displayed fa tty change and necrosis with an associated neutrophil polymorph infilt rate. Time course analysis revealed that plasma TNF-alpha (1-3 h post- LPS) and IL-6 (3 h post-LPS) bioactivity was significantly elevated in ethanol-fed compared with control-fed animals. No difference was seen in plasma IL-1 alpha concentration (maximal in both groups 6 h post-L PS). The expression of TNF-alpha, IL-1 alpha, IL-1 beta and IL-6 mRNA were elevated between 1 and 6 h post-LPS in the livers of both control and ethanol-fed rats. However, ethanol-fed LPS-treated animals exhibi ted significantly higher maximal expression of IL-1 and IL-6 mRNA. Com parison of the appearance of cytokine mRNA and plasma bioactivity indi cated an effect of ethanol feeding on post-transcriptional processing and/or the kinetics of the circulating cytokines. Elevated levels of b oth hepatic cytokine mRNA expression and the preceding plasma cytokine s are presumably a necessary prerequisite for hepatic injury seen in t his model and, therefore, possibly for the damage seen in human alcoho lics. Further studies using this model may lead to significant advance s in our understanding of the pathogenic mechanisms of alcoholic liver disease in humans.