TY - JOUR T1 - LSC 2012 abstract - The cell-penetrating P1pal-12 pepducin limits pulmonary fibrosis in the murine bleomycin model JF - European Respiratory Journal JO - Eur Respir J VL - 40 IS - Suppl 56 SP - 4530 AU - C. Lin AU - J.W. Duitman AU - K. Borensztajn AU - C.A. Spek Y1 - 2012/09/01 UR - http://erj.ersjournals.com/content/40/Suppl_56/4530.abstract N2 - Idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to available pharmacological therapies.Therefore, novel treatment options are urgently required. Protease-activated receptor (PAR)-1 is a heptahelical G protein-coupled receptor that mediates critical signaling pathways in pathology. Interestingly, bleomycin-induced lung fibrosis was shown to be diminished in PAR-1 deficient mice. We thus hypothesized that pharmacological PAR-1 inhibition may be an interesting therapeutic approach to combat pulmonary fibrosis. Consequently, we explored the effect of P1pal-12 (a pepducin blocking the PAR-1/G-protein interaction) during the development of lung fibrosis induced by intranasal instillation of bleomycin. We show that once daily treatment with 0.5, 2.5 or 10 mg/kg P1pal-12, reduced severity and extent of fibrotic lesions in a dose-dependent manner (2.5 and 2 fold reduction with 2.5 and 10 mg/kg). These findings correlated with significant decreases in fibronectin, collagen and ?-SMA mRNA expression levels in treated mice. Moreover, fibrin deposition in the lungs was reduced by 26% ± 3% (p<0.05) in 2.5 mg/kg treated mice compared to untreated controls. Finally,P1pal-12 reduced bleomycin-induced IL-6 and MCP-1 levels in lung homogenates by 65 ± 3% (p<0.01) and 36 ± 3% (p<0.05) respectively. Overall, our data show that P1pal-12 limits lung fibrosis suggesting that targeting PAR-1 may be a promising therapeutic strategy for pulmonary fibrosis. ER -