Endothelin-1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-β1

Raksha Jain, Philip W. Shaul, Zea Borok, Brigham C. Willis

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

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-β1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1-induced EMT is attenuated by a TGF-β1-neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A-mediated TGF-β1 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.

Original languageEnglish (US)
Pages (from-to)38-47
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume37
Issue number1
DOIs
StatePublished - Jul 1 2007

Keywords

  • Alveolar epithelial cells
  • Lung injury
  • Polar secretion
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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