title: Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical University of South Carolina, Charleston, SC 29425, USA. bogatkev@musc.edu
authors.forename: Galina S
authors.initials: GS
authors.lastname: Bogatkevich
authors.forename: Anna
authors.initials: A
authors.lastname: Ludwicka-Bradley
authors.forename: Richard M
authors.initials: RM
authors.lastname: Silver
mesh_terms: D000199:Actins / Q000378:metabolism; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D044463:Receptor, PAR-1 / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000925:Anticoagulants; D001562:Benzimidazoles; C526317:CCN2 protein, human; D011725:Pyridines; D044463:Receptor, PAR-1; D055513:Connective Tissue Growth Factor; D003094:Collagen; D013917:Thrombin; D000069604:Dabigatran