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.

Methods

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.

Results

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.

Conclusions

C5 inhibition effectively suppresses progression to ALF in mice models of fulminant hepatitis, serving as a new potential treatment strategy for ALF.

中文翻译：

---

补体 5 抑制阻止了小鼠模型中暴发性肝炎向急性肝衰竭的进展

背景与目标

急性肝功能衰竭 (ALF) 是一种危及生命的疾病，治疗选择有限。ALF 发病机制似乎涉及补体系统。然而，临床上尚未应用补体靶向干预。在这项研究中，我们旨在研究 Complement-5 (C5) 靶向 ALF 治疗的潜力。

方法

通过腹膜内脂多糖 (LPS) 和d-半乳糖胺 (D-GalN) 给药，在 C5 敲除 (KO, B10D2/oSn) 小鼠及其野生型 (WT) 对应物 (B10D2/nSn) 中诱导 ALF 。此后，静脉内施用单克隆抗C5抗体（Ab）或对照免疫球蛋白。此外，将选择性 C5a 受体 (C5aR) 拮抗剂施用于 WT 小鼠以比较其功效与抗 C5-Ab 介导的总 C5 抑制的功效。我们阐明了 LPS/D-GalN 攻击后延迟抗 C5-Ab 给药的治疗效果。我们还使用伴刀豆球蛋白-A 评估了抗 C5-Ab 在另一个 ALF 模型中的功效。

结果

LPS/D-GalN 给药后 6 小时肝损伤明显。C5-KO 和抗 C5-Ab 治疗显着提高了动物的总体存活率，显着降低了血清转氨酶和高迁移率 group box-1 的释放，减少了组织学组织损伤。这种改善的特点是 CD41+ 血小板聚集显着减少，F4/80+ 细胞得以维持，CD11+/Ly6-G+ 细胞浸润较少，细胞因子/趋化因子表达较低。此外，C5-KO 和抗 C5-Ab 在诱导显着肝损伤之前下调巨噬细胞产生的肿瘤坏死因子-α。此外，单链 DNA 细胞和半胱天冬酶活化减少，表明细胞凋亡显着减弱。抗 C5-Ab 治疗比 C5aR 拮抗剂更有效地保护肝脏，并且其延迟剂量具有保肝作用。

结论

C5抑制有效地抑制了暴发性肝炎小鼠模型中向ALF的进展，作为ALF的一种新的潜在治疗策略。