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The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice

Thrombin is a key player in the coagulation cascade, and it is attracting much attention as a promotor of cellular injured signaling. In ischemia/reperfusion injury (IRI), which is a severe complication of liver transplantation, thrombin may also promote tissue damage. The aim of this study is to re...

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Autores principales: Noguchi, Daisuke, Kuriyama, Naohisa, Hibi, Taemi, Maeda, Koki, Shinkai, Toru, Gyoten, Kazuyuki, Hayasaki, Aoi, Fujii, Takehiro, Iizawa, Yusuke, Tanemura, Akihiro, Murata, Yasuhiro, Kishiwada, Masashi, Sakurai, Hiroyuki, Mizuno, Shugo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984054/
https://www.ncbi.nlm.nih.gov/pubmed/33108682
http://dx.doi.org/10.1002/lt.25929
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author Noguchi, Daisuke
Kuriyama, Naohisa
Hibi, Taemi
Maeda, Koki
Shinkai, Toru
Gyoten, Kazuyuki
Hayasaki, Aoi
Fujii, Takehiro
Iizawa, Yusuke
Tanemura, Akihiro
Murata, Yasuhiro
Kishiwada, Masashi
Sakurai, Hiroyuki
Mizuno, Shugo
author_facet Noguchi, Daisuke
Kuriyama, Naohisa
Hibi, Taemi
Maeda, Koki
Shinkai, Toru
Gyoten, Kazuyuki
Hayasaki, Aoi
Fujii, Takehiro
Iizawa, Yusuke
Tanemura, Akihiro
Murata, Yasuhiro
Kishiwada, Masashi
Sakurai, Hiroyuki
Mizuno, Shugo
author_sort Noguchi, Daisuke
collection PubMed
description Thrombin is a key player in the coagulation cascade, and it is attracting much attention as a promotor of cellular injured signaling. In ischemia/reperfusion injury (IRI), which is a severe complication of liver transplantation, thrombin may also promote tissue damage. The aim of this study is to reveal whether dabigatran, a direct thrombin inhibitor, can attenuate hepatic IRI with focusing on a protection of sinusoidal endothelial cells (SECs). Both clinical patients who underwent hepatectomy and in vivo mice model of 60‐minute hepatic partial‐warm IRII, thrombin generation was evaluated before and after IRI. In next study, IRI mice were treated with or without dabigatran. In addition, hepatic SECs and hepatocytes pretreated with or without dabigatran were incubated in hypoxia/reoxygenation (H‐R) environment in vitro. Thrombin generation evaluated by thrombin–antithrombin complex (TAT) was significantly enhanced after IRI in the clinical study and in vivo study. Thrombin exacerbated lactate dehydrogenase cytotoxicity levels in a dose‐dependent manner in vitro. In an IRI model of mice, dabigatran treatment significantly improved liver histological damage, induced sinusoidal protection, and provided both antiapoptotic and anti‐inflammatory effects. Furthermore, dabigatran not only enhanced endogenous thrombomodulin (TM) but also reduced excessive serum high‐mobility group box‐1 (HMGB‐1). In H‐R models of SECs, not hepatocytes, pretreatment with dabigatran markedly attenuated H‐R damage, enhanced TM expression in cell lysate, and decreased extracellular HMGB‐1. The supernatant of SECs pretreated with dabigatran protected hepatocytes from H‐R damage and cellular death. Thrombin exacerbated hepatic IRI, and excessive extracellular HMGB‐1 caused severe inflammation‐induced and apoptosis‐induced liver damage. In this situation, dabigatran treatment improved vascular integrity via sinusoidal protection and degraded HMGB‐1 by endogenous TM enhancement on SECs, greatly ameliorating hepatic IRI.
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spelling pubmed-79840542021-03-24 The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice Noguchi, Daisuke Kuriyama, Naohisa Hibi, Taemi Maeda, Koki Shinkai, Toru Gyoten, Kazuyuki Hayasaki, Aoi Fujii, Takehiro Iizawa, Yusuke Tanemura, Akihiro Murata, Yasuhiro Kishiwada, Masashi Sakurai, Hiroyuki Mizuno, Shugo Liver Transpl Original Articles Thrombin is a key player in the coagulation cascade, and it is attracting much attention as a promotor of cellular injured signaling. In ischemia/reperfusion injury (IRI), which is a severe complication of liver transplantation, thrombin may also promote tissue damage. The aim of this study is to reveal whether dabigatran, a direct thrombin inhibitor, can attenuate hepatic IRI with focusing on a protection of sinusoidal endothelial cells (SECs). Both clinical patients who underwent hepatectomy and in vivo mice model of 60‐minute hepatic partial‐warm IRII, thrombin generation was evaluated before and after IRI. In next study, IRI mice were treated with or without dabigatran. In addition, hepatic SECs and hepatocytes pretreated with or without dabigatran were incubated in hypoxia/reoxygenation (H‐R) environment in vitro. Thrombin generation evaluated by thrombin–antithrombin complex (TAT) was significantly enhanced after IRI in the clinical study and in vivo study. Thrombin exacerbated lactate dehydrogenase cytotoxicity levels in a dose‐dependent manner in vitro. In an IRI model of mice, dabigatran treatment significantly improved liver histological damage, induced sinusoidal protection, and provided both antiapoptotic and anti‐inflammatory effects. Furthermore, dabigatran not only enhanced endogenous thrombomodulin (TM) but also reduced excessive serum high‐mobility group box‐1 (HMGB‐1). In H‐R models of SECs, not hepatocytes, pretreatment with dabigatran markedly attenuated H‐R damage, enhanced TM expression in cell lysate, and decreased extracellular HMGB‐1. The supernatant of SECs pretreated with dabigatran protected hepatocytes from H‐R damage and cellular death. Thrombin exacerbated hepatic IRI, and excessive extracellular HMGB‐1 caused severe inflammation‐induced and apoptosis‐induced liver damage. In this situation, dabigatran treatment improved vascular integrity via sinusoidal protection and degraded HMGB‐1 by endogenous TM enhancement on SECs, greatly ameliorating hepatic IRI. John Wiley and Sons Inc. 2020-12-09 2021-03 /pmc/articles/PMC7984054/ /pubmed/33108682 http://dx.doi.org/10.1002/lt.25929 Text en Copyright © 2020 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Noguchi, Daisuke
Kuriyama, Naohisa
Hibi, Taemi
Maeda, Koki
Shinkai, Toru
Gyoten, Kazuyuki
Hayasaki, Aoi
Fujii, Takehiro
Iizawa, Yusuke
Tanemura, Akihiro
Murata, Yasuhiro
Kishiwada, Masashi
Sakurai, Hiroyuki
Mizuno, Shugo
The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice
title The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice
title_full The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice
title_fullStr The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice
title_full_unstemmed The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice
title_short The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice
title_sort impact of dabigatran treatment on sinusoidal protection against hepatic ischemia/reperfusion injury in mice
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984054/
https://www.ncbi.nlm.nih.gov/pubmed/33108682
http://dx.doi.org/10.1002/lt.25929
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