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 & Rheumatology (Impact Factor: 7.87). 05/2011; 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.

0 Followers
 · 
173 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Organ fibrosis, the result of exaggerated, persistent, and often irreversible accumulation of extracellular matrix, complicates numerous diseases in all organs and tissues and has particularly serious consequences in the lungs. Abnormally accumulating scar tissue both replaces normally functioning parenchyma and distorts the architecture of unaffected tissue. In the lungs, the fibrotic process often leads to rapid and severe abnormalities in respiratory mechanics and gas exchange properties. There is no confirmed cure, and better therapies are required for treating fibrosis. The development of therapeutic strategies compels a better understanding of the cellular and molecular mechanisms of fibrosis, which are diverse, complex, and redundant. Epithelial injury, oxidative stress, coagulation disturbances, and inflammation are engaged in a complex interplay leading to augmented transformation of several cell types into myofibroblasts and prolonged survival of these extracellular matrix-producing cells. Cytokines are centrally engaged in the homeostatic and pathophysiologic regulation of connective tissue. Furthermore, it appears that identical cytokines are utilized by inflammation, profibrotic mechanisms, and the fibrotic process itself, suggesting that specific targeting or utilization of these cytokines holds therapeutic promise. In this article, we review the wealth of recent knowledge on major cytokines involved in the fibrotic process. Published by Elsevier Ltd.
    Cytokine 12/2014; DOI:10.1016/j.cyto.2014.11.008 · 2.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Zinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs.
    International Journal of Molecular Sciences 01/2015; 16(1):660-76. DOI:10.3390/ijms16010660 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Systemic sclerosis is a heterogeneous disease of unknown etiology with limited effective therapies. It is characterized by autoimmunity, vasculopathy, and fibrosis and is clinically manifested by multiorgan involvement. Interstitial lung disease is a common complication of systemic sclerosis and is associated with significant morbidity and mortality. The diagnosis of interstitial lung disease hinges on careful clinical evaluation and pulmonary function tests and high-resolution computed tomography. Effective therapeutic options are still limited. Several experimental therapies are currently in early-phase clinical trials and show promise. Copyright © 2015 Elsevier Inc. All rights reserved.
    Rheumatic Disease Clinics of North America 02/2015; 41(2). DOI:10.1016/j.rdc.2014.12.005 · 1.74 Impact Factor

Full-text (2 Sources)

Download
50 Downloads
Available from
May 21, 2014