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Published ahead of print on March 22, 2007, doi:10.1165/rcmb.2006-0353OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 1, July 2007, 38-47

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Submitted on September 19, 2006
Revised on March 20, 2007

Endothelin-1 Induces Alveolar EMT Through ET-A-mediated Production of Transforming Growth Factor-{beta}1

Raksha Jain1, Philip W Shaul2, Zea Borok3, and Brigham C Willis4*

1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA, 2 Department of Pediatrics, Division of Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA, 3 University of Southern California, Will Rogers Institute Pulmonary Research Center, Los Angeles, CA, USA, 4 Department of Pediatrics, Division of Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

* To whom correspondence should be addressed. 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 an autocrine or paracrine function for alveolar ET-1. In addition, ET-1 induces EMT through ET-A activation. Furthermore, TGF-{beta}1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1-induced EMT is attenuated by a TGF-{beta}1 neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A-mediated TGF-{beta}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.




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