Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis.
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.
Willis
Brigham C
BC
Department of Anesthesiology Critical Care Medicine, Childrens Hospital Los Angeles, California, USA.
Liebler
Janice M
JM
Luby-Phelps
Katherine
K
Nicholson
Andrew G
AG
Crandall
Edward D
ED
du Bois
Roland M
RM
Borok
Zea
Z
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
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