Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis

Am J Pathol. 2005 May;166(5):1321-32. doi: 10.1016/s0002-9440(10)62351-6.


The hallmark of idiopathic pulmonary fibrosis (IPF) is the myofibroblast, the cellular origin of which in the lung is unknown. We hypothesized that alveolar epithelial cells (AECs) may serve as a source of myofibroblasts through epithelial-mesenchymal transition (EMT). Effects of chronic exposure to transforming growth factor (TGF)-beta1 on the phenotype of isolated rat AECs in primary culture and a rat type II cell line (RLE-6TN) were evaluated. Additionally, tissue samples from patients with IPF were evaluated for cells co-expressing epithelial (thyroid transcription factor (TTF)-1 and pro-surfactant protein-B (pro-SP-B), and mesenchymal (alpha-smooth muscle actin (alpha-SMA)) markers. RLE-6TN cells exposed to TGF-beta1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-alpha (TNF-alpha). Exposure of rat AECs to TGF-beta1 (100 pmol/L) resulted in increased expression of alpha-SMA, type I collagen, vimentin, and desmin, with concurrent transition to a fibroblast-like morphology and decreased expression of TTF-1, aquaporin-5 (AQP5), zonula occludens-1 (ZO-1), and cytokeratins. Cells co-expressing epithelial markers and alpha-SMA were abundant in lung tissue from IPF patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-beta1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Aquaporin 5
  • Aquaporins / metabolism
  • Biomarkers / metabolism*
  • Cell Line
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelial Cells / physiology
  • Fibroblasts / pathology
  • Humans
  • Male
  • Membrane Proteins / metabolism
  • Mesoderm / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Nuclear Proteins / metabolism
  • Phenotype
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Thyroid Nuclear Factor 1
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1


  • AQP5 protein, human
  • Actins
  • Aqp5 protein, rat
  • Aquaporin 5
  • Aquaporins
  • Biomarkers
  • Membrane Proteins
  • NKX2-1 protein, human
  • Nkx2-1 protein, rat
  • Nuclear Proteins
  • TGFB1 protein, human
  • Tgfb1 protein, rat
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • smooth muscle actin, rat