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SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis
  1. Aparna Jayachandran1,
  2. Melanie Königshoff2,
  3. Haiying Yu1,
  4. Ewa Rupniewska1,
  5. Matthias Hecker1,
  6. Walter Klepetko3,
  7. Werner Seeger1,
  8. Oliver Eickelberg2,*
  1. 1 Department of Medicine, University of Giessen Lung Center, University of Giessen, Giessen, Germany;
  2. 2 Comprehensive Pneumology Center, Institute of Lung Biology and Disease (iLBD), Ludwig-Maximilians-U, Germany;
  3. 3 Department of Thoracic Surgery, University Hospital Vienna, Vienna, Austria, Germany
  1. Correspondence to: Oliver Eickelberg, Medicine II, University of Giessen Lung Center, Aulweg 123, Room 6-11, Giessen, 35392, Germany; oliver.eickelberg{at}helmholtz-muenchen.de

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix (ECM) deposition. The enhanced accumulation of (myo)fibroblasts may be attributed, in part, to the process of TGF-beta1-induced epithelial-mesenchymal transition (EMT), the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II (ATII) cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF.

Methods: Using quantitative RT-PCR, immunofluorescence, immunohistochemistry, Western blotting, as well as gain- and loss-of-function studies and functional assays, we assessed the role of SNAI1 and SNAI2 in TGF-beta1-induced EMT in ATII cells in vitro; and analysed the expression of SNAI transcription factors in experimental and idiopathic pulmonary fibrosis in vivo.

Results: TGF-beta1 treatment increased expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT and siRNA-mediated SNAI depletion attenuated TGF-beta1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human idiopathic pulmonary fibrosis and localised to hyperplastic ATII cells in vivo.

Conclusions: Our results demonstrate that TGF-beta1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and idiopathic pulmonary fibrosis in vivo suggest that SNAI-mediated EMT may contribute to the fibroblast pool in IPF.

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