Zhu Jianjun, Lu Tianfei, Yue Shi, Shen Xiuda, Gao Feng, Busuttil Ronald W, Kupiec-Weglinski Jerzy W, Xia Qiang, Zhai Yuan
1 Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA. 2 Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
Transplantation. 2015 Jan;99(1):48-55. doi: 10.1097/TP.0000000000000476.
Although rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined.
We determined how RPM impacted the pathogenesis of ischemia-reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death.
Rapamycin protected livers from IRI in the presence of fully developed liver inflammatory immune response. Rapamycin enhanced liver autophagy induction at the reperfusion stage. Dual mammalian (mechanistic) target of rapamycin (mTOR)1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers after reperfusion. Inactivation of Akt by Triciribine abolished the liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. Rapamycin, but not Trin 1, protected hepatocytes from stress and tumor necrosis factor-α induced cell death; and inhibition of autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection.
Rapamycin protected livers from IRI by both autophagy and mTORC2-Akt activation mechanisms.
尽管雷帕霉素（RPM）已在缺血模型中得到广泛研究，但其功能机制仍有待明确。
我们在小鼠肝脏部分温热缺血模型中确定了RPM如何影响缺血再灌注损伤（IRI）的发病机制，重点关注其对肝细胞死亡的调节。
在充分发展的肝脏炎性免疫反应存在的情况下，雷帕霉素可保护肝脏免受IRI损伤。雷帕霉素在再灌注阶段增强了肝脏自噬诱导。双重哺乳动物（机制性）雷帕霉素靶蛋白（mTOR）1/2抑制剂托林1尽管能够诱导自噬，但未能保护肝脏免受IRI损伤。用RPM而非托林1处理导致再灌注后肝脏中mTORC2-Akt信号通路激活增强。曲西立滨使Akt失活消除了RPM的肝脏保护作用。RPM和托林1的不同细胞保护作用在体外肝细胞培养中得到证实。雷帕霉素而非曲西立滨1保护肝细胞免受应激和肿瘤坏死因子-α诱导的细胞死亡；氯喹抑制自噬或曲西立滨抑制Akt消除了RPM介导的细胞保护作用。
雷帕霉素通过自噬和mTORC2-Akt激活机制保护肝脏免受IRI损伤。
