Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine ModelsSummary

• Main Authors: Jiro Kusakabe, Koichiro Hata, Hidetaka Miyauchi, Tetsuya Tajima, Yi Wang, Ichiro Tamaki, Junya Kawasoe, Yusuke Okamura, Xiangdong Zhao, Tatsuya Okamoto, Tatsuaki Tsuruyama, Shinji Uemoto
• Format: Article
• Language: English
• Published: Elsevier 2021-01-01
• Series: Cellular and Molecular Gastroenterology and Hepatology
• Subjects: Eculizumab; Anaphylatoxin; Membrane Attack Complex (MAC: C5b-9)
• Online Access: http://www.sciencedirect.com/science/article/pii/S2352345X21000011

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.