title: Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis.
abstract: 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.
authors.affiliation: Department of Anesthesiology Critical Care Medicine, Childrens Hospital Los Angeles, California, USA.
authors.forename: Brigham C
authors.initials: BC
authors.lastname: Willis
authors.forename: Janice M
authors.initials: JM
authors.lastname: Liebler
authors.forename: Katherine
authors.initials: K
authors.lastname: Luby-Phelps
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.forename: Roland M
authors.initials: RM
authors.lastname: du Bois
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D051402:Aquaporin 5; D020346:Aquaporins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D051402:Aquaporin 5; D020346:Aquaporins; D015415:Biomarkers; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C496036:AQP5 protein, human; C496040:Aqp5 protein, rat; C000614412:NKX2-1 protein, human; C000614416:Nkx2-1 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat