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Dabigatran inhibits thrombin's differentiation of lung fibroblasts to a myofibroblast phenotype
Author(s) -
Bogatkevich Galina S,
Silver Richard M
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1025.5
Subject(s) - myofibroblast , ctgf , thrombin , idiopathic pulmonary fibrosis , pulmonary fibrosis , fibrosis , lung , cancer research , extracellular matrix , pathology , dabigatran , connective tissue , interstitial lung disease , medicine , microbiology and biotechnology , chemistry , growth factor , immunology , receptor , biology , warfarin , platelet , atrial fibrillation
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 (PAR)‐1 and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts. Here we demonstrate that in a dose‐dependant manner dabigatran effectively inhibits thrombin‐induced differentiation of normal lung fibroblasts to the myofibroblast phenotype. As an active site inhibitor of thrombin, dabigatran restrains cleavage of the extracellular N‐terminal domain of PAR‐1 and prevents activation of PAR‐1 by the tethered ligand SFLLRN; however, dabigatran does not affect the activation of PAR‐1 by the selective agonist PAR‐1 activating peptide (PAR1‐AP). In normal lung fibroblasts dabigatran inhibits thrombin‐induced cell proliferation, α‐smooth muscle actin (α‐SMA) expression and organization, and the production of collagen and connective tissue growth factor (CTGF). Moreover, when treated with dabigatran scleroderma lung myofibroblasts produce less CTGF, α‐SMA, and collagen type I. We conclude that dabigatran restrains important profibrotic events in lung fibroblasts and can be considered to be a potential anti‐fibrotic drug for the treatment of fibrosing lung diseases, e.g. scleroderma lung disease and idiopathic pulmonary fibrosis.