1. Complement in Acute Liver Failure: The Right Timing to Give a Sincere Compliment
- Author
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Susanne N. Weber and Frank Lammert
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Cyt C, cytochrome c ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,8-OHdG, 8-hydroxy-2’-deoxyguanosine ,C5, complement component-5 ,RC799-869 ,Ab, antibody ,Anaphylatoxin ,Con-A, concanavalin A ,ALF, acute liver failure ,ALT, alanine aminotransferase ,ssDNA, single-stranded DNA ,Humans ,Medicine ,mAb, monoclonal antibody ,TNF-α, tumor necrosis factor α ,Original Research ,Membrane Attack Complex (MAC: C5b-9) ,KO, knockout ,Hepatology ,business.industry ,C5aR, C5a receptor ,Gastroenterology ,Liver failure ,D-GalN, d-galactosamine hydrochloride ,ELISA, enzyme-linked immunosorbent assay ,Liver Failure, Acute ,Eculizumab ,Diseases of the digestive system. Gastroenterology ,WT, wild-type ,IL, interleukin ,Complement (complexity) ,Immunology ,JNK, c-jun N-terminal kinase ,LPS, lipopolysaccharide ,MAC, membrane attack complex ,HMGB-1, high-mobility group box-1 ,business ,IgG, immunoglobulin - 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., Graphical abstract
- Published
- 2021
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