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J. Biol. Chem., Vol. 283, Issue 26, 17919-17928, June 27, 2008

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Inflammatory Levels of Nitric Oxide Inhibit Airway Epithelial Cell Migration by Inhibition of the Kinase ERK1/2 and Activation of Hypoxia-inducible Factor-1^*

Peter F. Bove, Milena Hristova, Umadevi V. Wesley, Nels Olson, Karen M. Lounsbury^¶, and Albert van der Vliet¹

From the Departments of Pathology, Microbiology and Molecular Genetics, and ^¶Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont 05405

Increased synthesis of NO during airway inflammation, caused by induction of nitric-oxide synthase 2 in several lung cell types, may contribute to epithelial injury and permeability. To investigate the consequence of elevated NO production on epithelial function, we exposed cultured monolayers of human bronchial epithelial cells to the NO donor diethylenetriaamine NONOate. At concentrations generating high nanomolar levels of NO, representative of inflammatory conditions, diethylenetriaamine NONOate markedly reduced wound closure in an in vitro scratch injury model, primarily by inhibiting epithelial cell migration. Analysis of signaling pathways and gene expression profiles indicated a rapid induction of the mitogen-activated protein kinase phosphatase (MPK)-1 and decrease in extracellular signal-regulated kinase (ERK)1/2 activation, as well as marked stabilization of hypoxia-inducible factor (HIF)-1 and activation of hypoxia-responsive genes, under these conditions. Inhibition of ERK1/2 signaling using U0126 enhanced HIF-1 stabilization, implicating ERK1/2 dephosphorylation as a contributing mechanism in NO-mediated HIF-1 activation. Activation of HIF-1 by the hypoxia mimic cobalt chloride, or cell transfection with a degradation-resistant HIF-1 mutant construct inhibited epithelial wound repair, implicating HIF-1 in NO-mediated inhibition of cell migration. Conversely, NO-mediated inhibition of epithelial wound closure was largely prevented after small interfering RNA suppression of HIF-1. Finally, NO-mediated inhibition of cell migration was associated with HIF-1-dependent induction of PAI-1 and activation of p53, both negative regulators of epithelial cell migration. Collectively, our results demonstrate that inflammatory levels of NO inhibit epithelial cell migration, because of suppression of ERK1/2 signaling, and activation of HIF-1 and p53, with potential consequences for epithelial repair and remodeling during airway inflammation.

Received for publication, December 4, 2007 , and in revised form, April 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL074295 and HL068865. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Pathology, College of Medicine, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405. Tel.: 802-656-8638; Fax: 802-656-8892; E-mail: Albert.van-der-Vliet{at}uvm.edu.

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