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(American Journal of Pathology. 2005;166:1321-1332.)
© 2005 American Society for Investigative Pathology

Induction of Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells by Transforming Growth Factor-ß1

Potential Role in Idiopathic Pulmonary Fibrosis

Brigham C. Willis*{dagger}{ddagger}, Janice M. Liebler{dagger}, Katherine Luby-Phelps§, Andrew G. Nicholson, Edward D. Crandall{dagger}, Roland M. du Bois and Zea Borok{dagger}

From the Department of Anesthesiology Critical Care Medicine,* Childrens Hospital Los Angeles, Los Angeles, California; the Division of Pulmonary and Critical Care Medicine,{dagger} Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California; the Division of Pediatric Critical Care Medicine,{ddagger} Department of Pediatrics, and the Department of Cell Biology,§ University of Texas Southwestern Medical School, Dallas, Texas; and Royal Brompton Hospital, Sydney Street, London, United Kingdom

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)-ß1 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-ß1 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-ß1 (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-ß1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.




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