Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan 430071, China.
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan 430071, China.
Int Immunopharmacol. 2021 Jul;96:107643. doi: 10.1016/j.intimp.2021.107643. Epub 2021 Apr 18.
Hepatic ischemia reperfusion (I/R) injury remains a major obstacle in liver transplantation, however an effective treatment to mitigate this injury is lacking. 25-Hydroxycholesterol (25HC) is a kind of oxysterol involved in inflammatory and immune responses. However, its function and the underlying mechanism on rat hepatic I/R injury has not been explored. A well-established rat model of partial warm ischemia reperfusion injury was performed. 25HC was intraperitoneally administrated 4 h before ischemia. The results verified that 25HC pretreatment effectively mitigated liver I/R injury, which was demonstrated by lower serum levels of transaminases, histology injury score and less apoptosis. Mechanistically, 25HC pretreatment activated PINK1/Parkin dependent mitophagy and inhibited the NLRP3 inflammasome. Via using mitophagy inhibitor 3-methyladenine (3-MA), we further found that 3-MA counteracted the protective effect of 25HC on hepatic I/R injury and the NLRP3 inflammasome. In conclusion, 25HC pretreatment ameliorates rat hepatic I/R injury, and this protective effect may be dependent on activating mitophagy and inhibiting NLRP3 inflammasome activation.
肝缺血再灌注（I/R）损伤仍然是肝移植的主要障碍，然而，缺乏有效的治疗方法来减轻这种损伤。25-羟基胆固醇（25HC）是一种参与炎症和免疫反应的氧化固醇。然而，其在大鼠肝 I/R 损伤中的功能及其潜在机制尚未得到探索。建立了部分热缺血再灌注损伤的大鼠模型。在缺血前 4 小时腹腔内给予 25HC。结果证实，25HC 预处理可有效减轻肝 I/R 损伤，表现为血清转氨酶水平降低、组织学损伤评分降低和细胞凋亡减少。机制上，25HC 预处理激活了 PINK1/Parkin 依赖性线粒体自噬，并抑制了 NLRP3 炎性小体。通过使用线粒体自噬抑制剂 3-甲基腺嘌呤（3-MA），我们进一步发现 3-MA 拮抗了 25HC 对肝 I/R 损伤和 NLRP3 炎性小体的保护作用。总之，25HC 预处理可改善大鼠肝 I/R 损伤，这种保护作用可能依赖于激活线粒体自噬和抑制 NLRP3 炎性小体的激活。
