Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; Organ Transplant Unit, Kyoto University Hospital, Kyoto, Japan.
Cell Mol Gastroenterol Hepatol. 2021;11(5):1351-1367. doi: 10.1016/j.jcmgh.2021.01.001. Epub 2021 Jan 12.
BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment.
ALF was induced in C5-knockout (KO, B10D2/oSn) mice and their wild-type (WT) counterparts (B10D2/nSn) through intraperitoneal lipopolysaccharide (LPS) and d-galactosamine (D-GalN) administration. Thereafter, monoclonal anti-C5 antibody (Ab) or control immunoglobulin was administered intravenously. Furthermore, a selective C5a-receptor (C5aR) antagonist was administered to WT mice to compare its efficacy with that of anti-C5-Ab-mediated total C5 inhibition. We clarified the therapeutic effect of delayed anti-C5-Ab administration after LPS/D-GalN challenge. We also assessed the efficacy of anti-C5-Ab in another ALF model, using concanavalin-A.
Liver injury was evident 6 hours after LPS/D-GalN administration. C5-KO and anti-C5-Ab treatment significantly improved overall animal survival and significantly reduced serum transaminase and high-mobility group box-1 release with decreased histological tissue damage. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and less infiltration of CD11+/Ly6-G+ cells with lower cytokine/chemokine expression. Furthermore, C5-KO and anti-C5-Ab downregulated tumor necrosis factor-α production by macrophages before inducing marked liver injury. Moreover, single-stranded-DNA cells and caspase activation were reduced, indicating significant attenuation of apoptosis. Anti-C5-Ab treatment protected the liver more effectively than the C5aR antagonist, and its delayed doses were hepatoprotective. In addition, anti-C5-Ab treatment was effective against concanavalin-A-induced ALF.
C5 inhibition effectively suppresses progression to ALF in mice models of fulminant hepatitis, serving as a new potential treatment strategy for ALF.
急性肝衰竭（ALF）是一种危及生命的疾病，治疗方法有限。ALF 的发病机制似乎涉及补体系统。然而，目前还没有针对补体的干预措施被应用于临床。本研究旨在探讨靶向补体 5（C5）治疗 ALF 的潜力。
通过腹腔内给予脂多糖（LPS）和 D-半乳糖胺（D-GalN）诱导 C5 敲除（KO，B10D2/oSn）小鼠和其野生型（WT）对照（B10D2/nSn）发生 ALF。此后，通过静脉内给予单克隆抗 C5 抗体（Ab）或对照免疫球蛋白。此外，还向 WT 小鼠给予选择性 C5a 受体（C5aR）拮抗剂，以比较其与抗 C5-Ab 介导的总 C5 抑制的疗效。我们阐明了 LPS/D-GalN 攻击后延迟给予抗 C5-Ab 的治疗效果。我们还评估了抗 C5-Ab 在另一种使用伴刀豆球蛋白 A（concanavalin-A）的 ALF 模型中的疗效。
LPS/D-GalN 给药后 6 小时出现明显的肝损伤。C5-KO 和抗 C5-Ab 治疗显著提高了整体动物存活率，并显著降低了血清转氨酶和高迁移率族蛋白 1 的释放，同时减少了组织学损伤。这种改善的特征是 CD41+血小板聚集减少，F4/80+细胞保持不变，CD11+/Ly6-G+细胞浸润减少，细胞因子/趋化因子表达降低。此外，C5-KO 和抗 C5-Ab 在诱导明显肝损伤之前可降低巨噬细胞中肿瘤坏死因子-α的产生。此外，单链 DNA 细胞和半胱天冬酶激活减少，表明细胞凋亡明显受到抑制。抗 C5-Ab 治疗比 C5aR 拮抗剂更有效地保护肝脏，且其延迟剂量具有肝保护作用。此外，抗 C5-Ab 治疗对伴刀豆球蛋白 A 诱导的 ALF 有效。
C5 抑制可有效抑制暴发性肝炎小鼠模型向 ALF 的进展，为 ALF 提供了一种新的潜在治疗策略。
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