title: Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner.
abstract: Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit an anti-inflammatory effect through binding to the high-mobility group box 1 protein (HMGB-1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild-type (WT) and toll-like receptor 4 (TLR-4) KO mice focusing on the HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR-4 and also HMGB-1 expression in liver cells, as well as release of HMGB-1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR-4 pathway-dependent manner.
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kadono
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hirao
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyauchi
authors.affiliation: Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iida
authors.affiliation: Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kanazawa
authors.affiliation: Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Mori
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Okajima
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Terajima
authors.affiliation: Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Uemoto
mesh_terms: D000818:Animals; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000150:complications*; D015398:Signal Transduction; D018180:Thrombomodulin / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D018180:Thrombomodulin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: basic (laboratory) research/science; liver transplantation/hepatology; macrophage/monocyte biology: activation; schemia reperfusion injury (IRI)