Publications (3)0 Total impact
Article: Ligation of protease-activated receptor 1 enhances αv β6 integrin-dependent TGF-β activation and promotes acute lung injury[show abstract] [hide abstract]
ABSTRACT: Activation of latent TGF-β by the αvβ6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which αvβ6-mediated TGF-β activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1 (PAR1), activate TGF-β in an αvβ6 integrin–specific manner. This effect is PAR1 specific and is mediated by RhoA and Rho kinase. Intratracheal instillation of the PAR1-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the αvβ6 integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-β activation; however, this is not observed in Itgb6–/– mice. Furthermore, Itgb6–/– mice are also protected from ventilator-induced lung edema. We also demonstrate that pulmonary edema and TGF-β activity are similarly reduced in Par1–/– mice following bleomycin-induced lung injury. These results suggest that PAR1-mediated enhancement of αvβ6-dependent TGF-β activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury, and they identify PAR1 and the αvβ6 integrin as potential therapeutic targets in this condition.Jenkins, R.G. and Su, X. and Su, G. and Scotton, C.J. and Camerer, E. and Laurent, G.J. and Davis, G.E. and Chambers, R.C. and Matthay, M.A. and Sheppard, D. (2006) Ligation of protease-activated receptor 1 enhances αv β6 integrin-dependent TGF-β activation and promotes acute lung injury. Journal of Clinical Investigation, 116 (6). pp. 1606-1614. ISSN 00219738.
Article: Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis[show abstract] [hide abstract]
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-ß-1 (TGF-ß1), 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.Howell, D.C.J. and Johns, R.H. and Lasky, J.A. and Shan, B. and Scotton, C.J. and Laurent, G.J. (2005) Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. American Journal of Pathology, 166 (5). pp. 1353-1365. ISSN 00029440.