title: Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.
abstract: OBJECTIVE
  Activation of the coagulation cascade leading to generation of thrombin has been documented extensively in various forms of lung injury, including that associated with systemic sclerosis. We previously demonstrated that the direct thrombin inhibitor dabigatran inhibits thrombin-induced profibrotic signaling in lung fibroblasts. This study was undertaken to test whether dabigatran etexilate attenuates lung injury in a murine model of interstitial lung disease.
  
  
  METHODS
  Lung injury was induced in female C57BL/6 mice by a single intratracheal instillation of bleomycin. Dabigatran etexilate was given as supplemented chow beginning on day 1 of bleomycin instillation (early treatment, study of antiinflammatory effect) or on day 8 following bleomycin instillation (late treatment, study of antifibrotic effect). Mice were killed 2 weeks or 3 weeks after bleomycin instillation, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were investigated.
  
  
  RESULTS
  Both early treatment and late treatment with dabigatran etexilate attenuated the development of bleomycin-induced pulmonary fibrosis. Dabigatran etexilate significantly reduced thrombin activity and levels of transforming growth factor β1 in BAL fluid, while simultaneously reducing the number of inflammatory cells and protein concentrations. Histologically evident lung inflammation and fibrosis were significantly decreased in dabigatran etexilate-treated mice. Additionally, dabigatran etexilate reduced collagen, connective tissue growth factor, and α-smooth muscle actin expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins.
  
  
  CONCLUSIONS
  Inhibition of thrombin using the oral direct thrombin inhibitor dabigatran etexilate has marked antiinflammatory and antifibrotic effects in a bleomycin model of pulmonary fibrosis. Our data provide preclinical information about the feasibility and efficacy of dabigatran etexilate as a new therapeutic approach for the treatment of interstitial lung disease.
authors.affiliation: Medical University of South Carolina, Charleston, SC, 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: Paul J
authors.initials: PJ
authors.lastname: Nietert
authors.forename: Tanjina
authors.initials: T
authors.lastname: Akter
authors.forename: Joanne
authors.initials: J
authors.lastname: van Ryn
authors.forename: Richard M
authors.initials: RM
authors.lastname: Silver
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D001761:Bleomycin; D000069604:Dabigatran; D004195:Disease Models, Animal; D005260:Female; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D001761:Bleomycin; D015091:beta-Alanine; D013917:Thrombin; D000069604:Dabigatran