Inhibition of Thrombin as a Novel Strategy in the Treatment of Scleroderma-Associated Interstitial Lung Disease

Abstract

Activation of the coagulation cascade leading to generation of thrombin has been extensively documented in various forms of lung injury including systemic sclerosisassociated interstitial lung disease (SSc-ILD). The molecular mechanisms underlying the pathogenesis and progression of lung fibrosis in SSc-ILD and in idiopathic pulmonary fibrosis (IPF) are not entirely clear. The conceptual process of fibrogenesis involves tissue injury and activation of the coagulation cascade, the release of various fibrogenic factors, and the induction of myofibroblasts culminating in enhanced extracellular matrix deposition. Cells with a myofibroblast phenotype appear in the early stages of fibrosis and are characterized by an increased proliferative capacity and abundant expression of ┙-SMA, collagens and other extracellular matrix proteins (Hinz et al., 2007). Myofibroblasts can be cultured from bronchoalveolar lavage (BAL) fluid of SSc-ILD patients, and thrombin activity is also significantly greater in BAL fluid from SSc-ILD patients compared with healthy controls (Ludwicka et al., 1992; Ohba et al., 1994). Thrombin differentiates lung fibroblasts to a myofibroblast phenotype, increases lung fibroblast proliferation (Bogatkevich et al., 2001), and enhances the proliferative effect of fibrinogen on fibroblasts (Gray et al., 1993). Thrombin is also a potent inducer of fibrogenic cytokines, such as transforming growth factor-┚ (TGF-┚) (Bachhuber et al., 1997), connective tissue growth factor (CTGF) (Chambers et al., 2000; Bogatkevich et al., 2006), platelet-derived growth factor-AA (PDGF-AA) (Ohba et al., 1994), chemokines (Mercer et al., 2007), and ECM proteins such as collagen, fibronectin, and tenascin in various cells, including lung fibroblasts (Tourkina et al., 2001; Chambers et al., 1998; Armstrong et al., 1996). Dabigatran is a selective direct thrombin inhibitor that reversibly binds to thrombin and prevents the cleavage of Arg-Gly bonds of fibrinogen needed for the formation of fibrin. Recently, we have demonstrated that binding of dabigatran to thrombin prevents cleavage of the extracellular N-terminal domain of the protease-activated receptor 1 (PAR-1), which is responsible for most profibrotic events induced by thrombin (Bogatkevich et al., 2009). In