Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats
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Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis.
Adult male Sprague–Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls.
In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension.
By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.
KeywordsDabigatran Thrombin Intrahepatic angiogenesis Liver fibrosis Portal pressure
The authors gratefully acknowledge Miss Chia-Li Chen for her technical assistance.
KC Lee, WF Hsu, and HC Lin conceived and designed the study. KC Lee, WF Hsu, YC Hsieh, and YY Yang analyzed and interpreted data. KC Lee and WF Hsu drafted the manuscript. KC Lee, WF Hsu, YH Huang, and HC Lin critically revised the article for important intellectual content. KC Lee, WF Hsu, YC Hsieh, YY Yang, YH Huang, and HC Lin approved the final approval of the article.
Research reported in this publication was supported by the Ministry of Science and Technology, Taiwan (NSC.104-2314-B-075-023-MY2), and the Taipei Veterans General Hospital (V103C-012).
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Conflict of interest
The authors declare that they have no competing interests.