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Protease activated receptor-1 regulates macrophage-mediated cellular senescence: a risk for idiopathic pulmonary fibrosis.
Lin, Cong; Rezaee, Farhad; Waasdorp, Maaike; Shi, Kun; van der Poll, Tom; Borensztajn, Keren; Spek, C Arnold.
Afiliación
  • Lin C; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
  • Rezaee F; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
  • Waasdorp M; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen,The Netherlands.
  • Shi K; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
  • van der Poll T; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
  • Borensztajn K; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
  • Spek CA; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Oncotarget ; 6(34): 35304-14, 2015 Nov 03.
Article en En | MEDLINE | ID: mdl-26474459
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-ß 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-ß activation and production. Finally, we show that the macrophage-dependent induction of PAR-1 driven TGF-ß 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Factores de Crecimiento Transformadores beta / Receptor PAR-1 / Fibrosis Pulmonar Idiopática / Macrófagos Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Oncotarget Año: 2015 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Factores de Crecimiento Transformadores beta / Receptor PAR-1 / Fibrosis Pulmonar Idiopática / Macrófagos Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Oncotarget Año: 2015 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos