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

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 11; no. 5; pp. 1351 - 1367
• Main Authors: Kusakabe, Jiro, Hata, Koichiro, Miyauchi, Hidetaka, Tajima, Tetsuya, Wang, Yi, Tamaki, Ichiro, Kawasoe, Junya, Okamura, Yusuke, Zhao, Xiangdong, Okamoto, Tatsuya, Tsuruyama, Tatsuaki, Uemoto, Shinji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; Elsevier
• Subjects: Anaphylatoxin; Animals; Antibodies, Monoclonal - pharmacology; Apoptosis; Complement C5 - antagonists & inhibitors; Complement C5 - immunology; Disease Models, Animal; Disease Progression; Eculizumab; Liver Failure, Acute - etiology; Liver Failure, Acute - pathology; Liver Failure, Acute - prevention & control; Macrophages - drug effects; Macrophages - immunology; Male; Massive Hepatic Necrosis - complications; Membrane Attack Complex (MAC: C5b-9); Mice; Original Research; Tumor Necrosis Factor-alpha - metabolism; Membrane Attack Complex (MAC: C5b-9); D-GalN; Ab; IL; KO; JNK; IgG; ALT; Cyt C; LPS; MAC; mAb; C5; Con-A; TNF-α; Eculizumab; ALF; Anaphylatoxin; C5aR; WT; ssDNA; 8-OHdG; ELISA; HMGB-1
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2021.01.001

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. [Display omitted]