Effect of rapamycin on hepatic ischemia reperfusion injury in rats and its possible mechanism / 中华肝胆外科杂志

ABSTRACT

Objective To analyze the effects of different doses of rapamycin on hepatic ischemia reperfusion injury in rats and the possible mechanism.Methods 48 Sprague-Dawley rats were randomly divided into four groups(n=12),low dose group (preoperative injection of low dose of rapamycin+ischemia),high dose group (preoperative high dose of rapamycin injection + ischemia),model group (preoperative injection of 0.9％ sodium chloride solution + ischemia),sham group (preoperative injection of 0.9％ sodium chloride solution,only dissected the first hepatic portal).Serum was collected 24 and 72 hours after surgery,ALT,AST,TNF-α and IL-6 concentrations were detected,Western blotting and PCR were performed to detect the expression of autophagy proteins,and HE staining was performed.Results 24 h after the operation,the liver tissue of the sham group was almost normal,the hepatic lobule structure of the model group disappeared,the liver cells were edema,vacuolar degeneration and necrosis,and the damage was reduced in the low dose and high dose group.24 h after surgery,levels of ALT,AST,TNF-α and IL-6 was on a declining curve in all groups,with statistically significant differences (P＜0.05).24 h after surgery,the relative expression levels of ULK1 (1.00±0 vs.4.76±2.62 vs.8.26±3.46 vs.12.95±6.45),microtubuleassociated protein 1 light chain 3(LC3,1.00±0 vs.2.88±0.59 vs.4.66± 1.22 vs.7.10±0.85) mRNA in sham group,model group,low dose group and high dose group were increased.While the relative mRNA expression levels of mammalian target of rapamycin (mTOR,1.00±0 vs.0.31 ±0.09 vs.0.18±0.04 vs.0.02± 0.01),P70 ribosomal protein kinase (S6K1,1.00±0 vs.0.57±0.34 vs.0.27±0.14 vs.0.03±0.01) showed a decreasing trend,and the differences were statistically significant (P＜0.05).24 h after surgery,the relative expressions of ULK1 and LC3 proteins in sham group,model group,low dose group and high dose group increased,while the phosphorylation of mTOR,S6K1 and ULK1 decreased,with statistically significant differences (P＜0.05).72 h after the operation,the results were agreed with those at 24 h after the operation.Conclusion Rapamycin activates autophagy through mTORC1-ULK1 signaling pathway to reduce HIRI,and the protective effect of high dose is better than that of low dose.