URSODEOXYCHOLYL LYSOPHOSPHATIDYLETHANOLAMIDE PROTECTS AGAINST HEPATIC ISCHEMIA AND REPERFUSION INJURY IN MICE
URSODEOXYCHOLYL LYSOPHOSPHATIDYLETHANOLAMIDE PROTECTS AGAINST HEPATIC ISCHEMIA AND REPERFUSION INJURY IN MICE
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DOI：
10.1097/shk.0000000000000312
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发表时间：
2015-04-01
期刊：
影响因子：
3.1
通讯作者：
Chamulitrat, Walee
中科院分区：
文献类型：
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作者：
Wang, Jiliang;Deng, Xiuling;Chamulitrat, Walee
肝移植过程中发生的缺血再灌注（I/R）损伤引起严重的并发症，导致移植失败。我们设计了一种细胞保护剂，熊去氧胆酸溶血磷脂酰乙醇胺（UDCA-LPE），它可以促进培养的肝细胞系的存活，并抑制体内肝损伤模型中的细胞凋亡和炎症。在这里，我们发现UDCA-LPE通过激活Akt/糖原合成酶激酶3 β存活信号通路增加小鼠肝细胞的活力。我们进一步通过钳夹C57/BL 6小鼠肝叶缺血90 min，然后松开钳夹并再灌注2 h来检测UDCA-LPE是否可以保护小鼠肝脏I/R损伤。进行了两种UDCA-LPE治疗方案;在缺血前30分钟腹腔注射100 mg/kg UDCA-LPE单次剂量，在缺血前30分钟和再灌注前即刻给予50 mg/kg UDCA-LPE双倍剂量。使用组织学和肝酶测定，我们观察到肝I/R引起显著的肝坏死，在接受I/R的UDCA-LPE处理小鼠中肝坏死减少。熊去氧胆酸LPE同时保护I/R诱导的细胞凋亡（裂解的半胱天冬酶3，裂解的聚[ADP-核糖]聚合酶1），炎症（IL-1 β，CD 11b，趋化因子配体2和3，趋化因子受体2），和门静脉纤维化（α-平滑肌肌动蛋白，纤溶酶原激活物抑制剂1），通过Western印迹，定量实时聚合酶链反应和免疫组织化学分析确定。双倍剂量方案中UDCA-LPE的保护作用优于单次给药方案。因此，UDCA-LPE可促进小鼠肝细胞的存活，并保护肝I/R损伤，因此可用于肝移植环境中的治疗。
The ischemia and reperfusion (I/R) injury that occurs during liver transplantation causes severe complications leading to transplantation failure. We have designed a cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which promotes the survival of cultured hepatocellular cell lines and inhibits apoptosis and inflammation in the in vivo models of liver injury. Here, we show that UDCA-LPE increased the viability of mouse hepatocytes by activating the Akt/glycogen synthase kinase 3 beta survival signaling pathways. We further tested whether UDCA-LPE could protect hepatic I/R injury in mice by clamping liver lobes of C57/BL6 mice for 90 min of ischemia followed by unclamping and reperfusion for 2 h. Two regimens for UDCA-LPE treatment were carried out; with a single dose of 100 mg/kg UDCA-LPE intraperitoneally injected 30 min prior to ischemia and a double dose of 50 mg/kg UDCA-LPE given 30min prior to ischemia and just prior to reperfusion. Using histology and liver enzyme determination, we observed that hepatic I/R caused significant hepatic necrosis, which was decreased in UDCA-LPE-treated mice undergoing I/R. Ursodeoxycholyl LPE concomitantly protected against I/R-induced apoptosis (cleaved caspase 3, cleaved poly[ADP-ribose] polymerase 1), inflammation (IL-1 beta, CD11b, chemokine ligands 2 and 3, chemokine receptor 2), and portal fibrogenesis (alpha-smooth muscle actin, plasminogen activator inhibitor 1), as determined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses. The protection by UDCA-LPE was found to be better in the double-dose than in the single-dose regimen. Thus, UDCA-LPE promoted the survival of mouse hepatocytes and protected against hepatic I/R injury and thus may be of therapeutic use in liver transplantation settings.