Protease activated receptor-1 regulates macrophage-mediated cellular senescence: a risk for idiopathic pulmonary fibrosis |
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Authors: | Cong Lin Farhad Rezaee Maaike Waasdorp Kun Shi Tom van der Poll Keren Borensztajn C. Arnold Spek |
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Affiliation: | 1. Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands;2. Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands;3. Inserm UMR1152, Medical School Xavier Bichat, Paris, France;4. Département Hospitalo-universtaire FIRE and LabEx Inflamex, Paris, France |
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Abstract: | Idiopathic pulmonary fibrosis (IPF) is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 (PAR-1) recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR-1-mediated idiopathic pulmonary fibrosis. The number of macrophages were significantly reduced in lungs of PAR-1 antagonist (P1pal-12) treated animals upon bleomycin instillation. In line with these data, PAR-1 stimulation increased monocyte/macrophage recruitment in response to epithelium injury in in vitro trans-well assays. Moreover, macrophages induced fibroblasts migration, differentiation and secretion of collagen, which were inhibited in the presence of TGF-β receptor inhibitors. Interestingly, these profibrotic effects were partially inhibited by treatment with the PAR-1 inhibitor P1pal-12. Using shRNA mediated PAR-1 knock down in fibroblasts, we demonstrate that fibroblast PAR-1 contributes to TGF-β activation and production. Finally, we show that the macrophage-dependent induction of PAR-1 driven TGF-β activation was mediated by FXa. Our data identify novel mechanisms by which PAR-1 stimulation on different cell types can contribute to IPF and identify macrophages as key players in PAR-1 dependent development of this devastating disease. IPF may result from cellular senescence mediated by macrophages in the lung. |
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Keywords: | protease-activated receptor, pulmonary fibrosis, bleomycin, macrophages, cellular senescence, TGF-β , Gerotarget |
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