Participation of autophagy in the initiation of graft dysfunction after rat liver transplantation
Participation of autophagy in the initiation of graft dysfunction after rat liver transplantation
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DOI：
10.4161/auto.5.3.7650
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发表时间：
2009-04-01
期刊：
影响因子：
13.3
通讯作者：
Uchiyama, Yasuo
中科院分区：
文献类型：
--
作者：
Gotoh, Kunihito;Lu, Zhenhui;Uchiyama, Yasuo
肝移植术后冷缺血-热再灌注（CI/WR）损伤的分子机制一直是研究热点。然而，迄今为止报道的机制是有争议的，没有改善治疗结果。在这里，使用长时间的CI和大鼠肝移植原位移植，我们发现CI/WR损伤与自噬密切相关。到WR开始后15分钟，具有丰富的自噬体和自溶酶体的小块肝细胞频繁地从肝索分离并阻塞血窦，导致2小时内肝细胞大量坏死。细胞团包括TUNEL阳性的细胞核，而没有半胱天冬酶-3和-7活化。用磷脂酰肌醇3-激酶（PI 3 K）抑制剂渥曼青霉素或LY 294002抑制自噬，降低了受体大鼠的肝损伤和死亡率。为了阐明这种自噬途径的下游机制，用天冬氨酸和半胱氨酸蛋白酶抑制剂、胃酶抑制剂和亮抑酶肽处理肝移植物。这种治疗也显著提高了受体大鼠的存活率。这些数据表明，自噬相关的肝细胞死亡触发肝移植功能障碍。抑制自噬的保护作用可能为预防CI/WR肝损伤提供新的途径。
Better ways to prevent the cold ischemia-warm reperfusion (CI/WR) injury associated with liver transplantation are needed, and many investigations have focused on the molecular mechanisms of this injury. However, the mechanisms reported to date are controversial and no improvement in therapy has resulted. Here, using prolonged CI and orthotopic transplantation of rat liver grafts, we found that the CI/WR injury was closely associated with autophagy. By 15 minutes after the start of WR, small masses of hepatocytes that possessed abundant autophagosomes and autolysosomes frequently dissociated from the hepatic cords and obstructed the sinusoid, causing massive necrosis of hepatocytes within 2 hours. The cell masses included TUNEL-positive nuclei without caspase-3 and -7 activation. Autophagy suppression with the phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin or LY294002, reduced both liver damage and the mortality rate of recipient rats. To elucidate the downstream mechanisms of this autophagic pathway, liver grafts were treated with aspartic and cysteine proteinase inhibitors, pepstatin and leupeptin. This treatment also significantly improved the survival rate of recipient rats. These data suggest that autophagy-associated hepatocyte death triggers liver graft dysfunction. The protective effects of suppressing autophagy may suggest new ways to prevent CI/WR injury of the liver.