Protective Effect of Tacrolimus and Prostaglandin E1 in Ischemia-Reperfusion Injury of Rat Livers

ABSTRACT

BACKGROUND: Liver ischemia and reperfusion injury is associated with activation of several inflammatory pathways including cytokines, tumor necrosis factor (TNF) and cell-mediated tissue damage. tacrolimus causes a regulatory effect on some inflammatory pathways, such as cytokines, TNF, adhesion molecule and inflammatory cells. Prostaglandin E1 (PGE1) has shown vasodilatation by relaxing vascular smooth muscles and inhibits the effect of proinflammatory cytokines which could reduce leukocyte- sinusoidal and platelet-sinusoidal interactions. METHODS: Liver ischemia was induced in rats by occluding the vessels, the supplying median segment, and the left lateral segment with an aneurysmal clip for 60 minutes. The rats received tacrolimus (0.5 mg/kg, tacrolimus group) or PGE1 (100 ug/kg, PGE1 group) or normal saline (Control group) 30 and 5 minutes before ischemia and reperfusion of the liver, respectively. The serum ALT, nitric oxide, and TNF were determined at 1, 24, and 48 hours after reperfusion, and hepatic necrosis was determined at the same times by using HE staining and a microscopic grading system. RESULTS: 1) In the control group, the serum ALT and TNF levels had peak values at 1 hour and were gradually decreased, but the serum nitric-oxide level was gradually increased after the time of reperfusion (p<0.05). No necrosis existed at in one hour, but the tissue necrosis at 24 hours was higher than that at 48 hours (p<0.05). 2) At one hour, the tacrolimus group had significantly lower serum ALT and TNF levels and a higher serum nitric-oxide level in the liver compared with the control group, but the serum nitric-oxide level did not change significantly after reperfusion (p<0.05). The extent of hepatic necrosis was significantly inhibited in the tacrolimus group when compared with that in the control group and the PGE1 group (p<0.05). 3) The PGE1 group exhibited improved hepatic necrosis compared with the control group (p<0.05). The improved hepatic necrosis was reflected in reductions of the serum ALT and TNF and an increase in the serum nitric-oxide level. CONCLUSIONS: These result suggest that tacrolimus and PGE1 protect the liver against ischemia- reperfusion injury by reducing the serum TNF level and increasing the serum nitric-oxide level. The protective effect of tacrolimus is more beneficial than that of PGE1.