LONG-TERM ETHANOL-CONSUMPTION ALTERS THE HEPATIC RESPONSE TO THE REGENERATIVE EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA

The pathogenesis of chronic alcoholic liver disease is uncertain, but it may reflect an impaired wound healing response to ethanol-induced l iver injury. Cell-to-cell communication such as that mediated by the c ytokine tumor necrosis factor is necessary for successful liver regene ration and complete recovery from liver injury. Hence disruption of in tercellular regenerative signaling may contribute to the pathogenesis of chronic alcoholic liver disease. To test this hypothesis, the cytok ine and regenerative responses triggered by partial hepatectomy were c ompared in ethanol-fed rats and isocalorically maintained, pair-fed co ntrols. To further clarify the effect of ethanol on tumor necrosis fac tor-modulated regenerative effects, we evaluated some of the rats in e ach feeding group after pretreatment with antibodies to tumor necrosis factor. As expected, ethanol inhibited DNA synthesis and liver cell p roliferation after partial hepatectomy. Ethanol-associated inhibition of liver regeneration occurred despite apparently similar serum concen trations of the tumor necrosis factor-inducible cytokine interleukin-6 . Treatment with antibodies to tumor necrosis factor 1 hr before parti al hepatectomy inhibited post-partial hepatectomy induction of interle ukin-6 and liver regeneration in ethanol-fed and pair-fed rats. Howeve r, serum interleukin-6 was reduced more in ethanol-fed rats than in co ntrol rats (93% vs. 66%; p < 0.05). Antibodies to tumor necrosis facto r also inhibited hepatic DNA synthesis more in ethanol-fed rats than i n controls (85% vs. 50%; p < 0.05). In ethanol-fed rats, the increased effect of tumor necrosis factor antibody on post-partial hepatectomy DNA synthesis suggests heightened sensitivity of hepatocytes to tumor necrosis factor. Tumor necrosis factor antibody decreased hepatocyte p roliferation more (93%) in ethanol-fed rats than in controls (62%) (p < 0.05). In contrast, proliferation of liver nonparenchymal cells was less inhibited in ethanol-fed rats (11%) than in controls (66%) (p < 0 .05). These data indicate that long-term ethanol feeding alters cell r esponsiveness to tumor necrosis factor during liver regeneration. Such ethanol-induced alterations in cell response to cytokines may disrupt intercellular communications and impede normal liver regeneration.