title: BMP-7 attenuated silica-induced pulmonary fibrosis through modulation of the balance between TGF-β/Smad and BMP-7/Smad signaling pathway.
abstract: OBJECTIVE
  To investigate the anti-fibrotic effects and possible mechanisms of bone morphogenetic protein-7 (BMP-7) on silica induced fibrosis in RLE-6TN cells, and compare the preventive treatment of experimental silicosis with BMP-7 with therapeutic treatment of silicosis in vitro models.
  
  
  METHODS
  RLE-6TN cells were incubated with the supernatant of RAW264.7, treated by 50 μg/mL silica in either presence or absence of BMP-7 in different phases. Morphological changes and the cellular wound-healing assays were used to evaluate the process of EMT. By using Western Blotting, the epithelial marker E-cadherin (E-cad), and the mesenchymal markers Vimentin (Vim), Snail, and fibronectin (FN) were detected as well as the Smad signaling pathway proteins, including phosphorylated Smad1/5(P-Smad1/5), phosphorylated Smad2/3(P-Smad2/3), and non-phosphorylated Smad1, Smad8, and Smad2. The progress of fibrosis was assessed by the content of hydroxyproline (Hyp) and collagen I and III protein levels. In addition, MTT assay was used to explore the toxic effects of silica as well as BMP-7.
  
  
  RESULTS
  The EMT model of RLE-6TN cells was established successfully, the cells had a fibroblast-like morphology with increasing migration activity. The expressions of Vim, Snail, FN, collagen I and collagen III were up-regulated with the increase of silica concentration. BMP-7 could attenuate the decrease of P-Smad1/5 and the increase of P-Smad2/3, collagen I, collagen III, and FN via Smad signaling pathway. BMP-7 inhibited the mesenchymal-like responses in RLE-6TN cells, including cell migration, expression of fibrosis markers, and secretion of Hyp. Furthermore, the anti-fibrotic effects in the prevention group were more effective than treatment group.
  
  
  CONCLUSIONS
  The restoration of BMP signaling with BMP-7 is associated with inhibiting silica-induced fibrosis through the mechanisms of activated BMP-7/Smad and suppressed TGF-β/Smad pathways. Preventive treatment of pulmonary fibrosis progression with BMP-7 may expect to be the optimized strategy than therapeutic therapy of fibrosis.
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Di
authors.initials: D
authors.lastname: Liang
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Gengxia
authors.initials: G
authors.lastname: Yang
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: An
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Piye
authors.initials: P
authors.lastname: Niu
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China. Electronic address: tian_lin@163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Tian
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology*; D008168:Lung / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000009:adverse effects*; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D055419:Bone Morphogenetic Protein 7; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D012822:Silicon Dioxide
keywords: Bone morphogenetic protein-7; Fibrosis; Silica