Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia-Reperfusion Injury in Mice
Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia-Reperfusion Injury in Mice
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DOI：
10.1002/hep.30241
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发表时间：
2019-08-01
期刊：
影响因子：
13.5
通讯作者：
Martin-Sanz, Paloma
中科院分区：
文献类型：
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作者：
Motino, Omar;Frances, Daniel E.;Martin-Sanz, Paloma
肝缺血再灌注损伤（IRI）是影响肝移植预后的重要临床问题。IRI可导致高达10%的早期器官衰竭，并易于发生慢性排斥反应。环氧合酶-2（考克斯-2）参与了多种肝脏疾病的发生，但考克斯-2在IRI中的意义仍存在争议。本研究旨在阐明肝细胞中考克斯-2诱导对肝脏IRI的作用。在本工作中，肝细胞特异性考克斯-2转基因小鼠（h考克斯-2-Tg）和他们的野生型（Wt）同窝出生的小鼠进行IRI。hCOX-2-Tg小鼠表现出比Wt小鼠更低的坏死和炎症等级，部分原因是减少了肝脏募集和中性粒细胞浸润，同时促炎细胞因子的血清水平降低。此外，hCOX-2-Tg小鼠表现出显着衰减的IRI诱导的氧化应激和肝细胞凋亡的增加，自噬通量的增加，并减少内质网应激相比，野生型小鼠。有趣的是，Wt小鼠的缺血预处理类似于在h考克斯-2-Tg小鼠中观察到的对IRI的有益作用，这是由于预处理引起的内源性考克斯-2的增加，其主要位于肝细胞中。此外，对接受肝移植患者血浆中前列腺素E-2（PGE（2））水平的测量显示，PGE（2）水平与移植物功能显著正相关，与缺血时间呈负相关。结论：这些数据支持肝考克斯-2诱导的保护作用以及随后衍生的异甘草素对IRI的升高的观点。
Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E-2 (PGE(2)) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE(2) levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.