EVIDENCE THAT FK506 ALLEVIATES ISCHEMIA-REPERFUSION INJURY TO THE RAT-LIVER - IN-VIVO DEMONSTRATION FOR SUPPRESSION OF TNF-ALPHA PRODUCTION IN RESPONSE TO ENDOTOXEMIA

The mechanism by which FK506 (FK) prevents hepatic injury induced by ischemia/reperfusion was studied. Adult Sprague-Dawley rats were subjected to 60-min normothermic liver ischemia. Animals were divided into two groups: group I, controls, saline vehicle treatment; group II, FK treatment. FK (1 mg/kg/day, p.o.) was given for 4 consecutive days prior to inducing ischemia. In addition to a survival study, plasma levels of endotoxin and serum activities of tumor necrosis factor-alpha (TNF) and aspartate aminotransferase (AST) were assessed in the blood collected from suprahepatic vena cava. Results showed: (1) FK therapy significantly improved 7-day survival (80.0%) compared with nontreated animals (50.0%, p < 0.05); (2) both TNF and endotoxin were elevated following reperfusion, reaching maximum values at 3 h after reperfusion (217.0 +/- 40.6 and 280.5 +/- 31.4 pg/ml, respectively, in the control; mean +/- SEM), and (3) serum activities of TNF and AST following reperfusion were substantially suppressed with FK treatment, whereas FK did not reduce the rise in endotoxin. These findings suggest that suppression of TNF production in response to endotoxemia might account at least in part for the protective effect of FK against ischemia-induced hepatic injury.