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 ischemia-reperfusion injury (IRI) with focusing on a protection of sinusoidal endothelial cells (SECs). In a clinical study of patients underwent hepatectomy and 60-min hepatic partial-warm IRI model in vivo, thrombin generation was evaluated before and after IRI. Subsequently, 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 LDH cytotoxicity levels in a dose-dependent manner in vitro. In IRI model of mice, dabigatran treatment significantly improved liver histological damage, induced sinusoidal protection, and provided both antiapoptotic and antiinflammatory 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 hepatocyte, pretreatment with dabigatran markedly attenuated H/R damage, enhanced TM expression in cell lysate, decreased extracellular HMGB-1. Interestingly, the supernatant of SECs pretreated with dabigatran protected hepatocytes from H/R damage and cellular death. In conclusion, thrombin exacerbated hepatic IRI, and excessive extracellular HMGB-1 caused severe inflammation- 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, finally ameliorated hepatic IRI.
This article is protected by copyright. All rights reserved.

References

PubMed