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

• DOI: 10.1152/ajplung.00007.2009
• Publication Date: 2009-10-03T13:55:20Z
• Authors: Guofei Zhou; Laura A. Dada; Minghua Wu; Aileen Kelly; Humberto Trejo; Qiyuan Zhou; John Varga; Jacob I. Sznajder
• Keywords: Hypoxia; Mitochondrial ROS; Hypoxia-Inducible Factors

Patients with acute lung injury develop hypoxia, which may lead to dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes pulmonary fibrosis. We sought determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). found induced the expression of alpha-smooth muscle actin (alpha-SMA) vimentin decreased E-cadherin transformed primary human, rat, mouse AEC, suggesting AEC. Both severe moderate EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced Moreover, alpha-SMA was mitochondria-deficient rho(0) cells, are incapable ROS production during hypoxia. CoCl(2) dimethyloxaloylglycine, two compounds stabilize hypoxia-inducible factor (HIF)-alpha under normoxia, failed induce Furthermore, overexpression constitutively active HIF-1alpha did not alpha-SMA. However, loss or HIF-2alpha abolished induction mRNA Hypoxia increased levels transforming growth (TGF)-beta1, preincubation AEC SB431542, an inhibitor TGF-beta1 type I receptor kinase, EMT, process dependent. both HIF-alpha were necessary for upregulation. Accordingly, we provided evidence through mitochondrial ROS, HIF, endogenous signaling.