FK 506 ameliorates normothermic liver ischemia in rats by suppressing production of tumor necrosis factor.

In recent years, there has been growing evidence that tumor necrosis factor-alpha (TNF) plays an important role in the development of hepatic injury after ischemia-reperfusion. We have previously demonstrated that the immunosuppressants, cyclosporine, azathioprine and FK506 (FK), have a protective effect on warm ischemic injury of the rat liver. In the present study, we attempted to elucidate the mechanism for the beneficial effect of FK on liver ischemia, with special reference to the suppression of TNF production. After 60 min and 90 min of warm liver ischemia, the survival rates were significantly improved by FK pretherapy. This was associated with amelioration of hepatic injury, as assessed by histological examinations and determinations of serum AST and lipid peroxide levels in the liver. After 60 min of liver ischemia, TNF was measurable during the reperfusion period in the sera of the control animals, peaking of 6 h after reperfusion (123 +/- 15.8 pg/ml, mean SEM). In contrast, pretreatment with FK significantly suppressed the elevation of serum TNF levels at the same time point (75.8 +/- 13.1 pg/ml, P < 0.05). The present data showed that liver ischemia-reperfusion resulted in TNF production, and that FK could protect the liver from reperfusion injury by suppressing this production of TNF.