Endothelin-1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-beta1

Am J Respir Cell Mol Biol. 2007 Jul;37(1):38-47. doi: 10.1165/rcmb.2006-0353OC. Epub 2007 Mar 22.


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-beta1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1-induced EMT is attenuated by a TGF-beta1-neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A-mediated TGF-beta1 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Endothelin-1 / physiology*
  • Epithelium / physiology*
  • Gene Expression Regulation*
  • Lung / metabolism
  • Lung / pathology
  • Lung Injury
  • Male
  • Mesoderm / physiology*
  • Models, Biological
  • Phenotype
  • Pulmonary Fibrosis / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A / metabolism
  • Receptor, Endothelin A / physiology*
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / physiology*


  • Endothelin-1
  • Receptor, Endothelin A
  • Transforming Growth Factor beta1