Lin Chengjie, Lei Biao, Dong Chunqiang, Chen Junze, Chen Shilian, Jiang Keqing, Zeng Yonglian, Su Huizhao, Jin Hu, Qiu Xiaoqiang, Li Zeyuan, Hu Zhigao, Yu Shuiping, Zhang Cheng, Lu Shiliu, Atkinson Carl, Tomlinson Stephen, Zhong Fudi, Yuan Guandou, He Songqing
Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China.
Am J Transplant. 2023 Apr;23(4):484-497. doi: 10.1016/j.ajt.2023.01.019. Epub 2023 Feb 4.
Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.
脑死亡（BD）供体是肝移植供体器官的主要来源。然而，BD对供体肝脏的影响以及肝移植后的结局仍不清楚。在此，我们在小鼠BD和肝移植模型中探究了补体的作用以及补体抑制对BD诱导的肝损伤和移植后损伤的治疗效果。对于补体抑制，我们使用了补体受体2（CR2）-Crry，一种特异性靶向补体激活位点的C3激活小鼠抑制剂。在小鼠模型中，BD导致供体肝脏补体激活和肝损伤以及移植后级联肝损伤，部分通过C3a-C3aR（C3a受体）信号通路介导，而CR2-Crry治疗可改善这种情况。用CR2-Crry治疗BD供体可提高移植物存活率，当受体在移植后额外接受一剂CR2-Crry时，存活率进一步提高。从机制上讲，我们确定补体抑制通过调节磷酸肌醇3-激酶（PI3K）信号通路减轻BD诱导的供体肝损伤和移植后级联损伤。总之，BD诱导供体肝损伤和移植后级联损伤，这是由作用于PI3K信号通路的补体激活产物介导的。我们的研究为制定提高肝移植中BD供体移植物存活率的策略提供了实验依据。
