西罗莫司对肝脏热缺血-再灌注损伤小鼠肝组织TLR4表达和细胞自噬功能的影响

目的 探讨西罗莫司对肝脏热缺血-再灌注(I/R)损伤小鼠肝组织Toll样受体4(TLR4)表达和细胞自噬功能的影响.方法 将40只Balb/c小鼠随机分为对照组、模型组、小剂量西罗莫司干预组(1 mg.kg-1)和大剂量西罗莫司干预组(3 mg.kg-1),每组10只,采用手术夹闭小鼠Glison鞘左支和中支1 h构建...

Effects of sirolimus on hepatic TLR4 expression and autophagy in mice with partial hepatic warm ischemia-reperfusion injury

Objective The aim of this study was to explore the effects of sirolimus on hepatic Toll-like receptor 4 (TLR4) expression and autophagy in mice with partial hepatic warm ischemia-reperfusion (I/R) injury. Methods Forty Balb/c mice were randomly divided into control, model, low-dose (1 mg.kg^-1) and high-dose (3 mg.kg^-1) of sirolimus group, with 10 mice in each group. The left and middle branches of Glison sheath were surgically clamped to construct partial hepatic warm I/R model. The mice in the intervention group were intraperitoneally injected with sirolimus 2 days before modeling. After 6 hours of reperfusion, serum tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were detected by ELISA. The expression of TLR4, nuclear factor κB (P65), phosphorylated P65 (p-P65), microtubule-associated protein 1 light chain 3B-II (LC3B-II) and P62 protein in liver tissues was detected by Western blot. The autophagosomes were detected by fluoroscopic electron microscope. Results After 6 h of reperfusion, serum ALT, AST, TNF-α and IL-6 levels in the model group were (1,370.6±245.7) U/L, (1,584.3±321.5) U/L, (69.4±8.8) pg/ mL and (154.1±22.7) pg/mL, significantly higher than in the control group, while serum ALT and AST levels in low-dose and high-dose of sirolimus-intervened groups were significantly lower than those in the model group (P<0.05); the hepatic expression of TLR4 protein and p-p65/p65 ratio in the model group were significantly stronger than those in the control group (P<0.05), while the expression of TLR4 protein and p-p65/p65 ratio in the low-dose and high-dose of sirolimus-intervened groups were significantly weaker than those in the model group (P<0.05), the expression of LC3B-II and P62 proteins, and the number of autophagosomes were significantly stronger or higher than those in the model group (P<0.05). Conclusion Sirolimus might reduce inflammatory response by inhibiting the activation of TLR4/NF-κB signaling pathway, which could effectively protect partial hepatic warm I/R injury in mice by inducing autophagy of hepatocytes.