Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Alexion Pharmaceuticals Inc., New Haven, CT.
Transplantation. 2020 Oct;104(10):2065-2077. doi: 10.1097/TP.0000000000003302.
Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI.
C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant.
C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases.
Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI.
肝缺血/再灌注损伤（IRI）是肝外科手术，包括肝移植的严重并发症。补体激活似乎与肝IRI密切相关；然而，尚无针对补体的干预措施在临床上得到应用。我们研究了针对补体 5（C5）的调节在肝 IRI 中的治疗潜力。
C5 敲除（B10D2/oSn）及其相应的野生型小鼠（WT，B10D2/nSn）在缺血前 30 分钟接受 90 分钟的部分（70%）肝缺血/再灌注，并用抗小鼠 C5 单克隆抗体（BB5.1）或相应的对照免疫球蛋白进行处理。WT 还给予 C5a 受体 1 拮抗剂以鉴定 C5a 或 C5b-9 哪个级联占主导地位。
C5 敲除和 WT 中 C5-Ab 的给药均显著降低了再灌注后 2 小时的血清转氨酶释放和组织病理学损伤。这种改善的特征是 CD41+血小板聚集减少，F4/80+细胞保持不变，高迁移率族蛋白 1（HMGB1）释放减少。再灌注 6 小时后，抗 C5-Ab 显著减轻了 CD11+和 Ly6-G+细胞浸润、细胞因子/趋化因子表达、单链 DNA+细胞和 cleaved caspase-3 表达。C5a 受体 1 拮抗剂与抗 C5-Ab 一样有效降低转氨酶。
抗 C5 抗体显著改善了肝 IRI，主要通过 C5a 介导的级联反应，不仅在早期通过抑制血小板聚集，而且在再灌注后期通过减轻浸润的巨噬细胞/中性粒细胞的激活和肝细胞凋亡来实现。鉴于其疗效、临床可用性和可控性，针对 C5 的干预可能为肝 IRI 提供一种新的治疗策略。
