DHA attenuates hepatic ischemia reperfusion injury by inhibiting pyroptosis and activating PI3K/Akt pathway
DHA attenuates hepatic ischemia reperfusion injury by inhibiting pyroptosis and activating PI3K/Akt pathway
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DHA 通过抑制焦亡和激活 PI3K/Akt 通路减轻肝脏缺血再灌注损伤
DOI：
10.1016/j.ejphar.2018.07.054
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发表时间：
2018-09-15
影响因子：
5
通讯作者：
Tong, Liquan
中科院分区：
文献类型：
--
作者：
Li, Ziyi;Zhao, Fazhang;Tong, Liquan
肝脏缺血再灌注(I/R)损伤在肝移植和大型肝脏手术中非常常见，可导致肝功能衰竭甚至死亡。二十二碳六烯酸(DHA)在许多疾病中显示出减少氧化应激和炎症反应的活性。本研究旨在探讨DHA对大鼠脑缺血再灌注损伤的保护作用及其机制。在这里，我们表明DHA通过降低天冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)水平以及减轻肝组织中的氧化应激来保护肝脏I/R损伤。低氧/复氧(H/R)可使水牛肝(BRL)细胞活力降低，但DHA可使BRL细胞活力恢复。DHA可显著下调下睑下垂相关蛋白NLRP3(NLRP3)、凋亡斑点蛋白样蛋白CARD(ASC)和裂解caspase-1的表达，减少促炎细胞因子的分泌。末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)染色支持上述结果。然而，与磷脂酰肌醇-3-激酶(PI3K)的特异性抑制剂LY294002孵育后，DHA的作用消失，因为它增加了裂解的caspase-1的表达和炎性细胞因子的产生。研究结果表明，DHA通过PI3K/Akt通路在体内和体外均能抑制肝脏I/R损伤时肝细胞的下垂，从而减轻I/R所致的肝损伤，为预防I/R肝损伤提供了一种潜在的治疗选择。
Hepatic ischemia reperfusion (I/R) injury is very common in liver transplantation and major liver surgeries and may cause liver failure or even death. Docosahexaenoic acid (DHA) has displayed activities in reducing oxidative stress and inflammatory reaction in many disorders. In the present study, we investigated the protective effects of DHA against I/R-induced injury and the underlying mechanisms. Here, we show that DHA protected hepatic I/R injury by reducing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and decreasing the oxidative stress in liver tissues. The viability of Buffalo rat liver (BRL) cells was reduced by hypoxia/ restoration (H/R) but restored by DHA. DHA significantly downregulated the expression of pyroptosis-related proteins including NLR pyrin domain containing 3 (NLRP3), apoptotic speck-like protein containing CARD (ASC) and cleaved caspase-1 and reduced the secretion of pro-inflammatory cytokines. The above results were supported by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. However, incubation with LY294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), abolished the effects of DHA, since it increased the expression of cleaved caspase-1 and the production of inflammatory cytokines. The present results have demonstrated that DHA ameliorated I/R-induced injury by inhibiting pyroptosis of hepatocytes induced in liver I/R injury in vivo and in vitro through the PI3K/Akt pathway, providing a potential therapeutic option to prevent liver injury by I/R.