Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine Models
Jiro Kusakabe, Koichiro Hata, Hidetaka Miyauchi, Tetsuya Tajima, Yi Wang, Ichiro Tamaki, Junya Kawasoe, Yusuke Okamura, Xiangdong Zhao, Tatsuya Okamoto, Tatsuaki Tsuruyama, Shinji Üemoto
Abstract
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.