Lee S C, Kim K H, Kim O H, Lee S K, Kim S J
Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea.
Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea.
Am J Transplant. 2016 Jul;16(7):2042-54. doi: 10.1111/ajt.13729. Epub 2016 Mar 10.
As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia-reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRI in relation with autophagy. The effects of everolimus were investigated in both in vitro and in vivo hepatic IRI models. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI-induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule-associated protein 1 light chain 3 and p62) and decreased pro-apoptotic proteins (cleaved caspase 3 and cleaved poly-ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si-autophagy-related protein 5, abrogated these anti-apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI-induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro-apoptotic proteins, (2) inhibiting the release of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-α), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRI by way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI.
由于肝脏捐赠标准已扩大到包括边缘供体，肝移植受者特别容易受到肝脏缺血再灌注损伤（IRI）。然而，尚未验证有任何具体措施可改善肝脏IRI。在本文中，我们探讨了依维莫司是否通过自噬对肝脏IRI具有保护作用。在体外和体内肝脏IRI模型中研究了依维莫司的作用。使用小鼠肝细胞AML12细胞和BALB/c小鼠建立每个模型。在IRI诱导的AML12细胞中，依维莫司处理增加了自噬标志物（微管相关蛋白1轻链3和p62）的表达，并降低了促凋亡蛋白（裂解的半胱天冬酶3和裂解的聚ADP核糖聚合酶）。使用巴弗洛霉素A1或自噬相关蛋白5 siRNA阻断自噬，消除了依维莫司的这些抗凋亡作用。随后，对肝脏IRI诱导的小鼠给予依维莫司具有肝脏保护作用，表现为：（1）降低促凋亡蛋白的表达；（2）抑制促炎细胞因子（IL-6和肿瘤坏死因子-α）的释放；（3）降低升高的肝酶（天冬氨酸转氨酶、丙氨酸转氨酶和氨）；（4）恢复肝脏组织病理学。这些发现表明，依维莫司通过激活自噬保护肝脏免受肝脏IRI的影响，因此可能是肝脏IRI的潜在治疗药物。
