Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

Guofei Zhou, Laura A. Dada, Minghua Wu, Aileen Kelly, Humberto Trejo, Qiyuan Zhou, John Varga, Jacob I. Sznajder

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of α-smooth muscle actin (α-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat, and mouse AEC, suggesting that hypoxia induces EMT in AEC. Both severe hypoxia and moderate hypoxia induced EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced EMT. Moreover, hypoxia-induced expression of α-SMA and vimentin was prevented in mitochondria-deficient ρ0 cells, which are incapable of ROS production during hypoxia. CoCl2 and dimethyloxaloylglycine, two compounds that stabilize hypoxiainducible factor (HIF)-α under normoxia, failed to induce α-SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1α did not induce α-SMA. However, loss of HIF-1α or HIF-2α abolished induction of α-SMA mRNA during hypoxia. Hypoxia increased the levels of transforming growth factor (TGF)-β1, and preincubation of AEC with SB431542, an inhibitor of the TGF-β1 type I receptor kinase, prevented the hypoxia-induced EMT, suggesting that the process was TGF-β1 dependent. Furthermore, both ROS and HIF-α were necessary for hypoxia-induced TGF-β1 upregulation. Accordingly, we have provided evidence that hypoxia induces EMT of AEC through mitochondrial ROS, HIF, and endogenous TGF-β1 signaling.

Original languageEnglish (US)
Pages (from-to)L1120-L1130
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume297
Issue number6
DOIs
StatePublished - Dec 2009

Keywords

  • Alveolar epithelial cells
  • Pulmonary fibrosis
  • Transforming growth factor-β1

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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