Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts

Arthritis Rheum. 2009 Nov;60(11):3455-64. doi: 10.1002/art.24935.


Objective: Myofibroblasts are the principal mesenchymal cells responsible for tissue remodeling, collagen deposition, and the restrictive nature of lung parenchyma associated with pulmonary fibrosis. We previously reported that thrombin activates protease-activated receptor 1 (PAR-1) and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts. We undertook this study to investigate whether a selective direct thrombin inhibitor, dabigatran, interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR-1.

Methods: Lung fibroblast proliferation was analyzed using the Quick Cell Proliferation Assay. Expression and organization of alpha-smooth muscle actin (alpha-SMA) was studied by immunofluorescence staining and immunoblotting. Contractile activity of lung fibroblasts was measured by a collagen gel contraction assay. Connective tissue growth factor (CTGF) and type I collagen expression was analyzed on Western blots.

Results: Dabigatran, at concentrations of 50-1,000 ng/ml, inhibited thrombin-induced cell proliferation, alpha-SMA expression and organization, and the production of collagen and CTGF in normal lung fibroblasts. Moreover, when treated with dabigatran (1 microg/ml), scleroderma lung myofibroblasts produced 6-fold less alpha-SMA, 3-fold less CTGF, and 2-fold less type I collagen compared with untreated cells.

Conclusion: Dabigatran restrains important profibrotic events in lung fibroblasts and warrants study as a potential antifibrotic drug for the treatment of fibrosing lung diseases such as scleroderma lung disease and idiopathic pulmonary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Anticoagulants / pharmacology*
  • Anticoagulants / therapeutic use
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Collagen / metabolism
  • Connective Tissue Growth Factor / metabolism
  • Dabigatran
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Lung / pathology*
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Receptor, PAR-1 / metabolism
  • Scleroderma, Systemic / drug therapy
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Signal Transduction / drug effects
  • Thrombin / antagonists & inhibitors*
  • Thrombin / pharmacology


  • ACTA2 protein, human
  • Actins
  • Anticoagulants
  • Benzimidazoles
  • CCN2 protein, human
  • Pyridines
  • Receptor, PAR-1
  • Connective Tissue Growth Factor
  • Collagen
  • Thrombin
  • Dabigatran