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Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats

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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.

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Acknowledgments

The authors gratefully acknowledge Miss Chia-Li Chen for her technical assistance.

Funding

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).

Author information

Author notes

  1. Kuei-Chuan Lee and Wei-Fan Hsu have contributed equally to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan

    Kuei-Chuan Lee, Yun-Cheng Hsieh, Che-Chang Chan, Yi-Hsiang Huang, Ming-Chih Hou & Han-Chieh Lin

  2. Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Kuei-Chuan Lee, Yun-Cheng Hsieh, Che-Chang Chan, Ying-Ying Yang, Yi-Hsiang Huang, Ming-Chih Hou & Han-Chieh Lin

  3. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Wei-Fan Hsu & Yi-Hsiang Huang

  4. Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

    Wei-Fan Hsu

  5. Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Ying-Ying Yang

Authors
  1. Kuei-Chuan Lee
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Contributions

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.

Corresponding author

Correspondence to Han-Chieh Lin.

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The authors declare that they have no competing interests.

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Lee, KC., Hsu, WF., Hsieh, YC. et al. Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats. Dig Dis Sci 64, 102–112 (2019). https://doi.org/10.1007/s10620-018-5311-1

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  • DOI: https://doi.org/10.1007/s10620-018-5311-1

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