title: Stretch-induced Activation of Transforming Growth Factor-β1 in Pulmonary Fibrosis.
abstract: Recent findings suggesting transforming growth factor (TGF)-β1 activation by mechanical stimuli in vitro raised the question of whether this phenomenon was relevant in vivo in the context of pulmonary fibrosis.
  
  
  
  To explore the effect of mechanical stress on TGF-β1 activation and its signaling pathway in rat and human fibrotic lung tissue using a novel ex vivo model.
  
  
  
  Rat lung fibrosis was induced using transient gene expression of active TGF-β1. Lungs were harvested at Day 14 or 21 and submitted to various stimuli in a tissue bath equipped with a force transducer and servo-controlled arm.
  
  
  
  Fibrotic lung strips responded to tensile force by releasing active TGF-β1 from latent stores with subsequent increase in tissue phospho-Smad2/3. In contrast, measurable active TGF-β1 and phospho-Smad2/3 were not induced by mechanical stress in nonfibrotic lungs. Protease inhibition did not affect the release of active TGF-β1. A TGF-β1 receptor inhibitor, Rho-associated protein kinase inhibitor, and αv integrin inhibitor all attenuated mechanical stretch-induced phospho-Smad2/3 in fibrotic lung strips. Furthermore, the induction of phospho-Smad2/3 was enhanced in whole fibrotic rat lungs undergoing ventilation pressure challenge compared with control lungs. Last, tissue slices from human lung with usual interstitial pneumonia submitted to mechanical force showed an increase in TGF-β1 activation and induction of phospho-Smad2/3 in contrast with human nonfibrotic lungs.
  
  
  
  Mechanical tissue stretch contributes to the development of pulmonary fibrosis via mechanotransduced activation of TGF-β1 in rodent and human pulmonary fibrosis.
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.|3 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Froese
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.|3 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Chiko
authors.initials: C
authors.lastname: Shimbori
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.|3 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Bellaye
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.
authors.forename: Mark
authors.initials: M
authors.lastname: Inman
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Obex
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.
authors.forename: Safoora
authors.initials: S
authors.lastname: Fatima
authors.affiliation: 4 Division of Respiratory Medicine, City Hospital Campus, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Gisli
authors.initials: G
authors.lastname: Jenkins
authors.affiliation: 3 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.|3 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Kjetil
authors.identifier: 0000-0002-0202-735X
authors.initials: K
authors.lastname: Ask
authors.affiliation: 1 Firestone Institute for Respiratory Health, The Research Institute of St. Joseph's Hamilton, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|2 Department of Medicine and.|3 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1
keywords: mechanical stress; mechanotransduction; pulmonary fibrosis; transforming growth factor-β1; ventilation