Lin Cong, Rezaee Farhad, Waasdorp Maaike, Shi Kun, van der Poll Tom, Borensztajn Keren, Spek C Arnold
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.
Oncotarget. 2015 Nov 3;6(34):35304-14. doi: 10.18632/oncotarget.6095.
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.
特发性肺纤维化（IPF）是一种具有破坏性的疾病，部分原因是细胞过早或成熟衰老。蛋白酶激活受体-1（PAR-1）最近成为纤维化肺病中的关键成分。因此，我们旨在研究巨噬细胞在PAR-1介导的特发性肺纤维化中的作用。在博来霉素滴注后，用PAR-1拮抗剂（P1pal-12）处理的动物肺中巨噬细胞数量显著减少。与这些数据一致，在体外Transwell实验中，PAR-1刺激增加了对上皮损伤的单核细胞/巨噬细胞募集。此外，巨噬细胞诱导成纤维细胞迁移、分化和分泌胶原蛋白，而在存在转化生长因子-β（TGF-β）受体抑制剂的情况下这些作用受到抑制。有趣的是，用PAR-1抑制剂P1pal-12处理可部分抑制这些促纤维化作用。通过在成纤维细胞中使用短发夹RNA（shRNA）介导的PAR-1敲低，我们证明成纤维细胞PAR-1有助于TGF-β的激活和产生。最后，我们表明巨噬细胞依赖性诱导的PAR-1驱动的TGF-β激活是由凝血因子Xa（FXa）介导的。我们的数据确定了PAR-1刺激不同细胞类型可导致IPF的新机制，并确定巨噬细胞是这种毁灭性疾病PAR-1依赖性发展中的关键因素。IPF可能由肺中巨噬细胞介导的细胞衰老引起。
