Absence of Proteinase-Activated Receptor-1 Signaling Affords Protection from Bleomycin-Induced Lung Inflammation and Fibrosis

Abstract

Activation of the coagulation cascade is commonly observed in the lungs of patients with both acute and chronic inflammatory and fibrotic lung disorders, as well as in animal models of these disorders. The aim of this study was to examine the contribution of the major thrombin receptor, proteinase-activated receptor-1 (PAR-1), during the acute inflammatory and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Inflammatory cell recruitment and increases in bronchoalveolar lavage fluid (BALF) protein were attenuated by 56 +/- 10% (P < 0.05) and 53 +/- 12% (P < 0.05), respectively, in PAR-1-deficient (PAR-1-/-) mice compared with wild-type (WT) mice. PAR-1-/- mice were also protected from bleomycin-induced pulmonary fibrosis with total lung collagen accumulation reduced by 59 +/- 5% (P < 0.05). The protection afforded by PAR-1 deficiency was accompanied by significant reductions in pulmonary levels of the potent PAR-1-inducible proinflammatory and profibrotic mediators, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta-1 (TGF-beta1), and connective tissue growth factor/fibroblast-inducible secreted protein-12 (CTGF/FISP12). In addition, PAR-1 was highly expressed in inflammatory and fibroproliferative lesions in lung sections obtained from patients with fibrotic lung disease. These data show for the first time that PAR-1 signaling plays a key role in experimentally induced lung injury, and they further identify PAR-1 as one of the critical receptors involved in orchestrating the interplay between coagulation, inflammation, and remodeling in response to tissue injury.

Lysophosphatidic Acid Induces αvβ6 Integrin-Mediated TGF-β Activation via the LPA2 Receptor and the Small G Protein Gαq

“…26 It is also known that other activators of RhoA such as thrombin can both activate TGF-␤ via the ␣v␤6 integrin and promote fibrogenesis. 12,59,60 It is therefore possible that following lung injury, RhoA activators may act to promote pulmonary fibrosis, through structural cell contraction and TGF-␤ activation by various different integrins, in a cell-specific manner, although studies to test this hypothesis in vivo have yet to be performed.…”

Activation of cartilage matrix metalloproteinases by activated protein C

“…These antiinflammatory responses of APC are EPCRdependent and are largely mediated by cleavage of the protease-activated receptors (PARs) (6). While PAR-1 activation is antiinflammatory in some tissues (7), it is associated with disease progression in others (8). In the context of arthritis, PAR-1 activation may play a role in promoting joint inflammation and associated cartilage damage (9).…”

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

“…1A). Elevated levels of thrombin activity have been also observed in bleomycin-induced pulmonary fibrosis in mice (Howell et al, 2005). We found that the level of active thrombin in BAL fluid from bleomycin-treated mice was 35-fold higher (1.3 ± 0.1 ng/ml, mean ± SEM) compared to that in control mice treated with saline (46.1 ± 7.9 ng/ml, mean ± SEM; P < 0.01) (Fig.…”