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

1 Division of Pulmonary and Critical Care Medicine and ; 2 Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago; and ; 3 Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois Submitted 7 January 2009 ; accepted in final form 30 September 20...

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Published in:American journal of physiology. Lung cellular and molecular physiology 2009-12, Vol.297 (6), p.L1120-L1130
Main Authors: Zhou, Guofei, Dada, Laura A, Wu, Minghua, Kelly, Aileen, Trejo, Humberto, Zhou, Qiyuan, Varga, John, Sznajder, Jacob I
Format: Article
Language:English
Subjects:
Animals
Cell growth
Cell Line, Transformed
Epithelial Cells - metabolism
Epithelial Cells - pathology
Gene expression
Gene Expression Regulation
Humans
Hypoxia
Hypoxia - metabolism
Hypoxia - pathology
Hypoxia-Inducible Factor 1 - metabolism
Kinases
Lung diseases
Mesoderm - metabolism
Mesoderm - pathology
Mice
Mitochondria - metabolism
Patients
Pulmonary Alveoli - metabolism
Pulmonary Alveoli - pathology
Rats
Reactive Oxygen Species - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal transduction
Transforming Growth Factor beta1 - biosynthesis
Transforming Growth Factor beta1 - genetics
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Summary:1 Division of Pulmonary and Critical Care Medicine and ; 2 Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago; and ; 3 Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois Submitted 7 January 2009 ; accepted in final form 30 September 2009 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 -smooth muscle actin ( -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 -SMA and vimentin was prevented in mitochondria-deficient 0 cells, which are incapable of ROS production during hypoxia. CoCl 2 and dimethyloxaloylglycine, two compounds that stabilize hypoxia-inducible factor (HIF)- under normoxia, failed to induce -SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1 did not induce -SMA. However, loss of HIF-1 or HIF-2 abolished induction of -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- 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. alveolar epithelial cells; pulmonary fibrosis; transforming growth factor-β1 Address for reprint requests and other correspondence: J. I. Sznajder, Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern Univ., 240 E. Huron, McGaw Pavilion M-300, Chicago, IL 60611 (e-mail: j-sznajder{at}northwestern.edu ).
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00007.2009