Non-Haemostatic Role for Blood Coagulation Proteases and Their Receptor;

  • Published 2009

Abstract

Pulmonary fibrosis is the end stage of a heterogeneous group of disorders and is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium. There is increasing evidence from a number of studies that activation of the coagulation cascade, with the resultant generation of coagulation proteases, plays a central role in fibrotic lung disease that is associated with acute and chronic lung injury. Consistent with this finding, levels of thrombin are increased in bronchoalveolar lavage fluid from patients and in animal models of this disorder. In addition to its classical role in blood coagulation, thrombin exerts a number of proinflammatory and profibrotic cellular effects in vitro that are critically important in tissue repair processes. These cellular effects are predominantly mediated via proteolytic activation of the major thrombin receptor protease-activated receptor-1 (PAR-1). This has led us to hypothesize that the procoagulant and the downstream cellular effects of thrombin, which are initiated following receptor activation, may be important in promoting tissue fibrosis in vivo. T o examine this hypothesis, we assessed the effect of a direct thrombin inhibitor in bleomycin-induced pulmonary fibrosis in rats. Immunohistochemical studies showed that expression of thrombin and PAR-1 in lung tissue increased dramatically after intratracheal instillation of bleomycin, compared with saline-treated animals. After bleomycin instillation, there was a doubling in the amount of lung collagen after 14 days, which was preceded by elevations in al( I) procollagen and connective tissue growth factor (CTGF) mRNA levels. However, when bleomycin-treated animals concurrently received a continuous infusion of a direct

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Cite this paper

@inproceedings{2009NonHaemostaticRF, title={Non-Haemostatic Role for Blood Coagulation Proteases and Their Receptor;}, author={}, year={2009} }