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j.jcmgh.2021.01.001.pdf | 3.77 MB | Adobe PDF | 見る/開く |
タイトル: | Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine Models |
著者: | Kusakabe, Jiro Hata, Koichiro https://orcid.org/0000-0002-3609-6396 (unconfirmed) Miyauchi, Hidetaka https://orcid.org/0000-0003-0961-7130 (unconfirmed) Tajima, Tetsuya Wang, Yi Tamaki, Ichiro Kawasoe, Junya Okamura, Yusuke Zhao, Xiangdong https://orcid.org/0000-0002-0714-5064 (unconfirmed) Okamoto, Tatsuya Tsuruyama, Tatsuaki Uemoto, Shinji |
著者名の別形: | 日下部, 治郎 秦, 浩一郎 宮内, 英孝 田嶋, 哲也 玉木, 一路 川添, 准矢 岡村, 祐輔 岡本, 竜弥 趙, 向東 鶴山, 竜昭 上本, 伸二 |
キーワード: | Eculizumab Anaphylatoxin Membrane Attack Complex (MAC: C5b-9) |
発行日: | 2021 |
出版者: | Elsevier BV The AGA Institute |
誌名: | Cellular and Molecular Gastroenterology and Hepatology |
巻: | 11 |
号: | 5 |
開始ページ: | 1351 |
終了ページ: | 1367 |
抄録: | 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. |
著作権等: | © 2021 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license. |
URI: | http://hdl.handle.net/2433/277105 |
DOI(出版社版): | 10.1016/j.jcmgh.2021.01.001 |
PubMed ID: | 33444818 |
出現コレクション: | 学術雑誌掲載論文等 |
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