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Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats

  • Kuei-Chuan Lee
  • Wei-Fan Hsu
  • Yun-Cheng Hsieh
  • Che-Chang Chan
  • Ying-Ying Yang
  • Yi-Hsiang Huang
  • Ming-Chih Hou
  • Han-Chieh Lin
Original Article
  • 79 Downloads

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 Thrombin Intrahepatic angiogenesis Liver fibrosis Portal pressure 

Notes

Acknowledgments

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

Author’s contribution

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.

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

10620_2018_5311_MOESM1_ESM.doc (72 kb)
Supplementary material 1 (DOC 72 kb)

References

  1. 1.
    Friedman SL. Liver fibrosis—from bench to bedside. J Hepatol. 2003;38:S38–S53.CrossRefGoogle Scholar
  2. 2.
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669.CrossRefGoogle Scholar
  3. 3.
    Pinzani M, Milani S, De Franco R, et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology. 1996;110:534–548.CrossRefGoogle Scholar
  4. 4.
    Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology. 2009;50:1294–1306.CrossRefGoogle Scholar
  5. 5.
    Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258–264.CrossRefGoogle Scholar
  6. 6.
    Sullivan BP, Weinreb PH, Violette SM, Luyendyk JP. The coagulation system contributes to alphaVbeta6 integrin expression and liver fibrosis induced by cholestasis. Am J Pathol. 2010;177:2837–2849.CrossRefGoogle Scholar
  7. 7.
    Fiorucci S, Antonelli E, Distrutti E, et al. PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation. Hepatology. 2004;39:365–375.CrossRefGoogle Scholar
  8. 8.
    Rhea JM, Molinaro RJ. Direct thrombin inhibitors: clinical uses, mechanism of action, and laboratory measurement. MLO Med Lab Obs. 2011;43:20–22.PubMedGoogle Scholar
  9. 9.
    Kopec AK, Joshi N, Towery KL, et al. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther. 2014;351:288–297.CrossRefGoogle Scholar
  10. 10.
    Kassel KM, Sullivan BP, Cui W, Copple BL, Luyendyk JP. Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease. Am J Pathol. 2012;181:1287–1295.CrossRefGoogle Scholar
  11. 11.
    Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010;30:1885–1889.CrossRefGoogle Scholar
  12. 12.
    van Ryn J, Schurer J, Kink-Eiband M, Clemens A. Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation. Anesthesiology. 2014;120:1429–1440.CrossRefGoogle Scholar
  13. 13.
    Lee KC, Yang YY, Huang YT, et al. Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability. Clin Sci. 1979;119:45–55.CrossRefGoogle Scholar
  14. 14.
    Cerini F, Vilaseca M, Lafoz E, et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol. 2016;64:834–842.CrossRefGoogle Scholar
  15. 15.
    Blackburn JS, Brinckerhoff CE. Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. Am J Pathol. 2008;173:1736–1746.CrossRefGoogle Scholar
  16. 16.
    Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50:604–620.CrossRefGoogle Scholar
  17. 17.
    Gao JH, Wen SL, Yang WJ, et al. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. PloS One. 2013;8:e69309.CrossRefGoogle Scholar
  18. 18.
    Gao JH, Wen SL, Feng S, et al. Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats. Angiogenesis. 2016;19:501–511.CrossRefGoogle Scholar
  19. 19.
    Zhang J, Luo B, Tang L, et al. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome. Gastroenterology. 2009;136:1070–1080.CrossRefGoogle Scholar
  20. 20.
    Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology. 1995;21:1238–1247.PubMedGoogle Scholar
  21. 21.
    Violi F, Ferro D, Basili S, et al. Increased rate of thrombin generation in hepatitis C virus cirrhotic patients. Relationship to venous thrombosis. J Investig Med. 1995;43:550–554.PubMedGoogle Scholar
  22. 22.
    Marra F, Grandaliano G, Valente AJ, Abboud HE. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology. 1995;22:780–787.PubMedGoogle Scholar
  23. 23.
    Knight V, Tchongue J, Lourensz D, Tipping P, Sievert W. Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells. Hepatology. 2012;55:879–887.CrossRefGoogle Scholar
  24. 24.
    Kukla M. Angiogenesis: a phenomenon which aggravates chronic liver disease progression. Hepatol Int. 2013;7:4–12.CrossRefGoogle Scholar
  25. 25.
    Novo E, Cannito S, Zamara E, et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol. 2007;170:1942–1953.CrossRefGoogle Scholar
  26. 26.
    Mochizuki A, Pace A, Rockwell CE, et al. Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1alpha-dependent manner by modulating macrophage phenotype in mice. J Immunol. 2014;192:3847–3857.CrossRefGoogle Scholar
  27. 27.
    Zhao Y, Wang Y, Wang Q, Liu Z, Liu Q, Deng X. Hepatic stellate cells produce vascular endothelial growth factor via phospho-p44/42 mitogen-activated protein kinase/cyclooxygenase-2 pathway. Mol Cell Biochem. 2012;359:217–223.CrossRefGoogle Scholar
  28. 28.
    Wang Y, Huang Y, Guan F, et al. Hypoxia-inducible factor-1alpha and MAPK co-regulate activation of hepatic stellate cells upon hypoxia stimulation. PloS One. 2013;8:e74051.CrossRefGoogle Scholar
  29. 29.
    Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–156.CrossRefGoogle Scholar
  30. 30.
    Sogaard KK, Horvath-Puho E, Gronbaek H, Jepsen P, Vilstrup H, Sorensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol. 2009;104:96–101.CrossRefGoogle Scholar
  31. 31.
    Tripodi A, Fracanzani AL, Primignani M, et al. Procoagulant imbalance in patients with nonalcoholic fatty liver disease. J Hepatol. 2014;61:148–154.CrossRefGoogle Scholar
  32. 32.
    Villa E, Camma C, Marietta M, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143:e1251–e1254.CrossRefGoogle Scholar
  33. 33.
    Vilaseca M, Garcia-Caldero H, Lafoz E, et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology. 2017;65:2031–2044.CrossRefGoogle Scholar
  34. 34.
    De Gottardi A, Trebicka J, Klinger C, et al. Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. Liver Int. 2017;37:694–699.CrossRefGoogle Scholar
  35. 35.
    Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet. 2013;52:243–254.CrossRefGoogle Scholar
  36. 36.
    Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010;38:1567–1575.CrossRefGoogle Scholar
  37. 37.
    Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis: current status and future directions. J Hepatol. 2014;61:912–924.CrossRefGoogle Scholar
  38. 38.
    Bosch J, Berzigotti A, Garcia-Pagan JC, Abraldes JG. The management of portal hypertension: rational basis, available treatments and future options. J Hepatol. 2008;48:S68–S92.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • 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
    • 1
    • 2
  1. 1.Division of Gastroenterology and Hepatology, Department of MedicineTaipei Veterans General HospitalTaipei 112Taiwan
  2. 2.Department of Medicine, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Institute of Clinical Medicine, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  4. 4.Division of Hepato-Gastroenterology, Department of Internal MedicineChina Medical University HospitalTaichungTaiwan
  5. 5.Division of General Medicine, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan

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