Article

Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.

Medical University of South Carolina, Charleston, SC, USA.
Arthritis & Rheumatism (impact factor: 7.87). 02/2011; 63(5):1416-25. DOI:10.1002/art.30255
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

2 weeks
 
3 weeks
 
antifibrotic effects
 
BAL fluid
 
bleomycin instillation
 
bleomycin-induced lung fibrosis
 
bleomycin-induced pulmonary fibrosis
 
coagulation cascade
 
connective tissue growth factor
 
dabigatran etexilate attenuates lung injury
 
dabigatran etexilate-treated mice
 
female C57BL/6 mice
 
growth factor β1
 
Histologically evident lung inflammation
 
inflammatory cells
 
interstitial lung disease
 
lung injury
 
new therapeutic approach
 
single intratracheal instillation
 
α-smooth muscle actin expression