Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Center for Anatomical, Pathological, and Forensic Medical Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Front Immunol. 2023 Aug 16;14:1174243. doi: 10.3389/fimmu.2023.1174243. eCollection 2023.
Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation ( =0.010) and ssDNA+ cells (0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs ( =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines ( =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both 0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy ( =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.
肝脏缺血/再灌注损伤（IRI）常导致肝外科手术中的严重并发症，包括肝移植。补体激活似乎与肝 IRI 有关；然而，尚无针对补体的干预措施被临床应用。我们研究了 Properdin 靶向补体调节在肝 IRI 中的治疗潜力。雄性野生型（B10D2/nSn）小鼠经历 90 分钟的左叶和中叶部分肝 IRI，同时给予单克隆抗 Properdin 抗体（Ab）或对照免疫球蛋白（IgG）。由于补体系统与肝再生密切相关，因此在 70%部分肝切除的小鼠模型中还评估了抗 Properdin-Ab 对肝再生的影响。抗 Properdin-Ab 在再灌注后 2 和 6 小时显著降低血清转氨酶和组织病理学损伤（分别为 0.001）。这些 2 小时的改善伴随着 CD41+血小板聚集（=0.010）和 ssDNA+细胞（0.001）的显著减少，分别表明肝微循环和细胞凋亡得到了显著改善。特征性地，抗 Properdin-Ab 维持了代表巨噬细胞（主要为库普弗细胞）的 F4/80+细胞（=0.001）。Western blot 显示 MAPKs 中仅 Erk1/2 的磷酸化减少（=0.004）。再灌注 6 小时后，抗 Properdin-Ab 显著减弱了 HMGB-1 的释放，HMGB-1 会引发促炎细胞因子/趋化因子的释放（=0.002）。抗 Properdin-Ab 显著减轻了 CD11b+和 Ly6-G+细胞（分别代表浸润性巨噬细胞和中性粒细胞）的浸润（均为 0.001）。值得注意的是，抗 Properdin-Ab 对 70%部分肝切除后 48 小时的残余肝重和 BrdU+细胞没有影响（分别为 0.13 和 0.31）。结论： Properdin 抑制可显著改善肝 IRI，而不干扰肝再生。
