Zhu Cunle, Shi Shangheng, Jiang Peng, Huang Xijian, Zhao Jinxin, Jin Yan, Shen Yuntai, Zhou Xin, Liu Huan, Cai Jinzhen
The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China.
Organ Transplantation Center, The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
J Invest Surg. 2023 Dec;36(1):2164813. doi: 10.1080/08941939.2022.2164813.
Hepatic ischemia-reperfusion injury (IRI) is a common innate immune-mediated sterile inflammatory response in liver transplantation and liver tumor resection. Neutrophil extracellular traps (NETs) can aggravate liver injury and activates innate immune response in the process of liver IRI. However, Curcumin (Cur) can reverse this damage and reduce NETs formation. Nevertheless, the specific regulatory mechanism is still unclear in liver IRI. This study aimed to explore the potential mechanisms that how does Cur alleviate hepatic IRI by inhibits NETs production and develop novel treatment regimens.
We established a hepatic IRI model by subjecting C57BL/6J mice to 60 min of ischemia, followed by reperfusion for 2 h, 6 h, 12 h, and 24 h respectively. Subsequently, we were separated into 5 groups, namely the I/R group, Cur group, DNase-1 group, Cur + DNase1 group and sham operation group. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST), Hematoxylin-eosin staining, immunofluorescence, and TUNEL analysis were applied to assess liver injury degree and NETs levels. Western blot assay was used to detect the protein levels of apoptosis-related proteins and MEK pathway proteins.
Cur could alleviate hepatic IRI by inhibiting the generation of NETs via suppressing the MEK/ERK pathway. In addition, this study also revealed that DNase-1 is vital for alleviating hepatic IRI by reducing the generation of NETs.
Cur combined with DNase-1 was more effective than the two drugs administered alone in alleviating hepatic IRI by inhibiting the generation of NETs. These results also suggested that curcumin combined with DNase-1 was a potential therapeutic strategy to mitigate hepatic IRI.
肝缺血再灌注损伤（IRI）是肝移植和肝肿瘤切除术中常见的先天性免疫介导的无菌性炎症反应。中性粒细胞胞外陷阱（NETs）可加重肝损伤并在肝IRI过程中激活先天性免疫反应。然而，姜黄素（Cur）可逆转这种损伤并减少NETs的形成。尽管如此，肝IRI中具体的调节机制仍不清楚。本研究旨在探讨Cur通过抑制NETs产生减轻肝IRI的潜在机制，并开发新的治疗方案。
通过对C57BL/6J小鼠进行60分钟的缺血，然后分别再灌注2小时、6小时、12小时和24小时，建立肝IRI模型。随后，将其分为5组，即I/R组、Cur组、DNase-1组、Cur+DNase1组和假手术组。应用血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）、苏木精-伊红染色、免疫荧光和TUNEL分析来评估肝损伤程度和NETs水平。采用蛋白质印迹法检测凋亡相关蛋白和MEK通路蛋白的水平。
Cur可通过抑制MEK/ERK通路来抑制NETs的产生，从而减轻肝IRI。此外，本研究还表明DNase-1对于通过减少NETs的产生来减轻肝IRI至关重要。
Cur与DNase-1联合使用在通过抑制NETs产生减轻肝IRI方面比单独使用这两种药物更有效。这些结果还表明姜黄素与DNase-1联合使用是减轻肝IRI的一种潜在治疗策略。
