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Endothelin-1 Induces Alveolar Epithelial–Mesenchymal Transition through Endothelin Type A Receptor–Mediated Production of TGF-1

Department of Internal Medicine; Division of Pulmonary and Vascular Biology, Division of Neonatal-Perinatal Medicine, and Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, California

Correspondence and requests for reprints should be addressed to Brigham C. Willis, M.D., Assistant Professor of Pediatrics, Division of Pulmonary and Vascular Biology, Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063. E-mail: brigham.willis{at}utsouthwestern.edu

Endothelin-1 (ET-1) is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial–mesenchymal transition (EMT), which was recently demonstrated in alveolar epithelial cells (AEC), may play an important role in the pathogenesis of IPF and other forms of pulmonary fibrosis. Whether ET-1 contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of ET-1 and to determine if ET-1 induces EMT in AEC. We demonstrate that ET-1 is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors (ET-A) and, to a lesser extent, type B receptors (ET-B), suggesting autocrine or paracrine function for alveolar ET-1. In addition, ET-1 induces EMT through ET-A activation. Furthermore, TGF-1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1–induced EMT is attenuated by a TGF-1–neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A–mediated TGF-1 production. These findings increase our basic understanding of the role of ET-1 in pulmonary fibrosis and suggest potential roles for AEC-derived ET-1 in the pathogenesis of other alveolar epithelial–mediated lung diseases.

Key Words: pulmonary fibrosis • alveolar epithelial cells • polar secretion • lung injury

CLINICAL RELEVANCE Treatments for idiopathic pulmonary fibrosis (IPF) are not yet known. Our findings that endothelin-1 is produced by alveolar epithelial cells and induces alveolar epithelial-mesenchymal transition may lead to novel treatments for pulmonary fibrotic diseases such as IPF.