Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats

  • Dig Dis Sci. 2019 Jan;64(1):102-112. doi: 10.1007/s10620-018-5311-1.
Kuei-Chuan Lee  1  2 ,  Wei-Fan Hsu  3  4 ,  Yun-Cheng Hsieh  1  2 ,  Che-Chang Chan  1  2 ,  Ying-Ying Yang  2  5 ,  Yi-Hsiang Huang  1  2  3 ,  Ming-Chih Hou  1  2 ,  Han-Chieh Lin  6  7
Affiliations
  • 1. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.
  • 2. Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 3. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 4. Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 5. Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 6. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. [email protected].
  • 7. Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. [email protected].
PMID: 30288660 DOI: 10.1007/s10620-018-5311-1
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: By inhibiting Thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

Keywords
Dabigatran; Intrahepatic angiogenesis; Liver fibrosis; Portal pressure; Thrombin.
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