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: 7.48). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: A key question in both wound healing and fibrosis is the trigger for the initial formation of scar tissue. To help form scar tissue, circulating monocytes enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but fibrocyte differentiation is strongly inhibited by the plasma protein serum amyloid P (SAP), and healthy tissues contain very few fibrocytes. In wounds and fibrotic lesions, mast cells degranulate to release tryptase, and thrombin mediates blood clotting in early wounds. Tryptase and thrombin are upregulated in wound healing and fibrotic lesions, and inhibition of these proteases attenuates fibrosis. We report that tryptase and thrombin potentiate human fibrocyte differentiation at biologically relevant concentrations and exposure times, even in the presence of concentrations of serum and SAP that normally completely inhibit fibrocyte differentiation. Fibrocyte potentiation by thrombin and tryptase is mediated by protease-activated receptors 1 and 2, respectively. Together, these results suggest that tryptase and thrombin may be an initial trigger to override SAP inhibition of fibrocyte differentiation to initiate scar tissue formation. Copyright © 2014 by The American Association of Immunologists, Inc.
    Journal of immunology (Baltimore, Md. : 1950). 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Systemic sclerosis (SSc), or scleroderma, is a heterogeneous and complex autoimmune disease characterized by varying degrees of skin and organ fibrosis and obliterative vasculopathy. The disease results in significant morbidity and mortality, and to date, available treatments are limited. Lung involvement is the leading cause of death of patients with SSc. Over the past year, significant advances have been made in our understanding of SSc-associated lung disease, and this review attempts to encapsulate these most recent findings and place them in context.
    Current Opinion in Rheumatology 09/2014; · 5.07 Impact Factor
  • [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; · 2.87 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014