title: Protease activated receptor-1 regulates macrophage-mediated cellular senescence: a risk for idiopathic pulmonary fibrosis.
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.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cong
authors.initials: C
authors.lastname: Lin
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.|Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen,The Netherlands.
authors.forename: Farhad
authors.initials: F
authors.lastname: Rezaee
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Waasdorp
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Kun
authors.initials: K
authors.lastname: Shi
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.|Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|Département Hospitalo-universtaire FIRE and LabEx Inflamex, Paris, France.
authors.forename: Keren
authors.initials: K
authors.lastname: Borensztajn
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D000067996:RAW 264.7 Cells; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044463:Receptor, PAR-1; D018125:Receptors, Transforming Growth Factor beta
keywords: Gerotarget; bleomycin; cellular senescence; macrophages; protease-activated receptor; pulmonary fibrosis