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タイトル: Complement 5 Inhibition Ameliorates Hepatic Ischemia/reperfusion Injury in Mice, Dominantly via the C5a-mediated Cascade
著者: Kusakabe, Jiro
Hata, Koichiro  KAKEN_id  orcid https://orcid.org/0000-0002-3609-6396 (unconfirmed)
Tamaki, Ichiro
Tajima, Tetsuya
Miyauchi, Hidetaka  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-0961-7130 (unconfirmed)
Wang, Yi
Nigmet, Yermek
Okamura, Yusuke
Kubota, Toyonari
Tanaka, Hirokazu
Tsuruyama, Tatsuaki
Uemoto, Shinji
著者名の別形: 日下部, 治郎
秦, 浩一郎
玉木, 一路
田嶋, 哲也
宮内, 英孝
岡村, 祐輔
久保田, 豊成
田中, 宏和
鶴山, 竜昭
上本, 伸二
発行日: Oct-2020
出版者: Wolters Kluwer Health
誌名: Transplantation
巻: 104
号: 10
開始ページ: 2065
終了ページ: 2077
抄録: [Background. ] Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI. [Methods. ] C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant. [Results. ] C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases. [Conclusions. ] Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI.
著作権等: Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
URI: http://hdl.handle.net/2433/281528
DOI(出版社版): 10.1097/tp.0000000000003302
PubMed ID: 32384381
出現コレクション:学術雑誌掲載論文等

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