FK-506 PRETREATMENT IS ASSOCIATED WITH REDUCED LEVELS OF TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-6 FOLLOWING HEPATIC ISCHEMIA-REPERFUSION

Using a rat model, the effect of pre-treatment with FK 506 on hepatic ischemia/reperfusion injury was investigated. All control animals died within 72 h of the ischemia/reperfusion injury. Pre-treatment of the animals with FK 506 (0.3 mg/kg in 0.5 ml saline) administered intravenously improved survival. The most striking protection against fatal ischemia/reperfusion injury was achieved in rats that were given FK 506 6 and 24 h prior to the induction of the hepatic ischemic insult (70% and 80% 10-day survival rates, respectively). The hepatoprotective effect of FK 506 was assessed further in a second experiment in which the serum levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were measured. These results suggest that a 60-min period of hepatic ischemia and subsequent reperfusion triggers the release of both TNF and IL-6, and that FK 506 pre-treatment (6 h before the ischemic episode) significantly inhibits the production and/or release of these two cytokines compared to untreated controls. These data provide additional information concerning the immunosuppressive and hepatoprotective activities of FK 506. Based upon these data, it is probable that FK 506 attenuates hepatic ischemia/reperfusion injury, at least in part, by reducing TNF and IL-6 levels.