Thrombomodulin Administration Attenuates Ischemia-Reperfusion Injury of the Remnant Liver After 70% Hepatectomy in Rats: Simulated Model of Small-for-size Graft in Living Donor Liver Transplantation

Abstract

BackgroundHepatic ischemia-reperfusion injury (IRI) is a serious complication affecting liver function and postoperative course after liver transplantation. Thrombomodulin (TM) has been known to have anticoagulant and anti-inflammatory activities exerting a cytoprotective effect. We evaluated the cytoprotective effect of recombinant human soluble TM (rhsTM) on the remnant liver exposed to IRI after 70% hepatectomy in rats, which was the simulated model of small-for-size graft in living donor liver transplantation. Materials and MethodsA Wistar rat underwent 70% hepatectomy followed by 20-minute IRI for the remnant liver. rhsTM (1 mg/kg) (TM group) or saline (control group) was intravenously administered 30 minutes before operation. ResultsAlanine aminotransaminase levels were more significantly decreased during the 24 hours after operation in the TM group than in control group, especially at 6 hours. Intrahepatic infiltration of macrophages/monocytes (ED-1 immunohistochemical staining) at 6 hours was significantly decreased in the TM group compared to the control group. The number of proliferating cell nuclear antigen−positive cells at 12 hours (hepatocyte proliferation) was significantly higher in the TM group than in the control group; although liver weight 7 days after operation did not differ between the two groups. Hepatocyte apoptosis (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, also known as TUNEL assay) at 24 hours was more significantly diminished in the TM group than in the control group. ConclusionThese results suggest that rshTM attenuates hepatocyte injury through its anti-inflammatory effect, and promotes hepatocyte proliferation in the reduced-size liver exposed to hepatic IRI.