Evidence that FK506 Alleviates Ischemia/Reperfusion Injury to the Rat Liver: In vivo Demonstration for Suppression of TNF-α Production in Response to Endotoxemia

Abstract

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-α (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.

Cyclophilin D as a Drug Target

“…In most of the others, prevention of activation of NF-κB and cytokines is proposed to be involved. The same explanation is advanced for the protective effects of tacrolimus in rats [90][91][92][93] and dogs [94]). Further, both tacrolimus and CsA help maintain microcirculation in rat small intestine and to protect tissue from ischemia/reperfusion injury by decreasing the production and release of endothelin-1 [95].…”

Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation

“…23 Other studies have shown that tacrolimus pretreatment results in decreased expression of tumor necrosis factor-␣, IL-1, and IL-6. [23][24][25] More recently, it was documented to reduce expression of adhesion molecules, with a demonstrated reduction in leukocyte rolling and adhesion. 19 In conclusion, although complete elucidation of the role of tacrolimus in hepatic I/R injury deserves further investigation, in this trial, the first prospective randomized trial conducted in the clinical arena, we show that use of a flush solution containing tacrolimus results in superior early graft function and decreased hepatocellular injury.…”

Effects of tacrolimus on ischemia-reperfusion injury

“…50 Induction of HSP70 has been seen in rat kidneys after a low nonnephrotoxic dose of tacrolimus (0.3 mg/kg) administered intravenously, and these animals subsequently showed significantly better renal function when exposed to I-R injury. 72 The same study showed that tacrolimus-pretreated animals had better postischemic renal function than animals pretreated with cyclosporine A (3 mg/kg).…”