Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway.
Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway.
复制标题
重组脂联素通过激活 AMPK/eNOS 通路改善肝脏缺血再灌注损伤。
DOI：
10.1371/journal.pone.0066382
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
He X
中科院分区：
文献类型：
--
作者：
Zhang C;Liao Y;Li Q;Chen M;Zhao Q;Deng R;Wu C;Yang A;Guo Z;Wang D;He X
减少肝脏手术中的缺血再灌注（I/R）损伤具有重要意义。减少炎症反应是实现这一目标的有效途径。值得注意的是，脂联素（APN）被发现在心脏和肾脏I/R损伤中具有抗炎活性。在此，我们研究APN在肝I/R损伤中的作用。Wistar大鼠随机分为假手术组、I/R对照组、I/R+APN组和I/R +APN+AMPK抑制剂组。分别于再灌注后6 h和24 h取肝和血标本。评估肝功能和组织病理学变化。通过免疫组化染色检测巨噬细胞和中性粒细胞浸润，同时分别使用ELISA和RT-PCR测量肝脏中释放的促炎细胞因子和趋化因子。TUNEL染色和caspase-3表达检测肝细胞凋亡。Western blotting检测APN下游分子。循环APN在肝I/R过程中下调。当在肝I/R期间给予外源性APN时，观察到丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）降低，并且观察到较少的肝细胞坏死。与I/R对照组相比，I/R+APN组的炎性细胞浸润和促炎细胞因子/趋化因子释放也减少。APN治疗也减少了肝细胞凋亡，证明减少TUNEL阳性细胞和caspase-3的表达在再灌注肝。最后，AMPK/eNOS通路被发现被APN激活，并且AMPK抑制剂的施用逆转了APN的有益作用。APN可通过减少炎症反应和肝细胞凋亡来保护肝脏免受I/R损伤，这一过程可能涉及AMPK/eNOS通路。目前的研究为肝脏I/R损伤提供了潜在的药理学靶点。
It is of importance to minimize ischemia reperfusion (I/R) injury during liver operations. Reducing the inflammatory reaction is an effective way to achieve this goal. Notably, adiponectin (APN) was found to have anti-inflammatory activity in heart and renal I/R injury. Herein, we investigated the role of APN in liver I/R injury. Wistar rats were randomized to four groups: (1) sham group; (2) I/R control group; (3) I/R+APN group; and (4) I/R+APN+AMPK inhibitor group. Liver and blood samples were collected 6h and 24h after reperfusion. Liver function and histopathologic changes were assessed. Macrophage and neutrophil infiltration was detected by immunohistochemistry staining, while pro-inflammatory cytokines and chemokines released in the liver were measured using ELISA and RT-PCR, respectively. Apoptosis was analyzed by TUNEL staining and caspase-3 expression in the liver. Downstream molecules of APN were investigated by Western blotting. Circulatory APN was down-regulated during liver I/R. When exogenous APN treatment was administered during liver I/R, alanine transaminase (ALT) and aspartate aminotransferase (AST) were decreased, and less hepatocyte necrosis was observed. Less inflammatory cell infiltration and pro-inflammatory cytokines/chemokines release were also observed in the I/R+APN group when compared with the I/R control group. APN treatment also reduced hepatocyte apoptosis, evidenced by reduced TUNEL positive cells and less caspase-3 expression in the reperfused liver. Finally, the AMPK/eNOS pathway was found to be activated by APN, and administration of an AMPK inhibitor reversed the beneficial effects of APN. APN can protect the liver from I/R injury by reducing the inflammatory response and hepatocyte apoptosis, a process that likely involves the AMPK/eNOS pathway. The current study provides a potential pharmacologic target for liver I/R injury.