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J. Biol. Chem. 282 (5): 3213-3220

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Airway Epithelial Cell Migration and Wound Repair by ATP-mediated Activation of Dual Oxidase 1*

Umadevi V. Wesley{ddagger}1, Peter F. Bove§1, Milena Hristova§, Sean McCarthy§, , and Albert van der Vliet§2

Departments of §Pathology and {ddagger}Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405

Abstract: The airway epithelium is continuously subjected to environmental pollutants, airborne pathogens, and allergens and relies on several intrinsic mechanisms to maintain barrier integrity and to promote epithelial repair processes following injury. Here, we report a critical role for dual oxidase 1 (Duox1), a newly identified NADPH oxidase homolog within the tracheobronchial epithelium, in airway epithelial cell migration and repair following injury. Activation of Duox1 during epithelial injury is mediated by cellular release of ATP, which signals through purinergic receptors expressed on the epithelial cell surface. Purinergic receptor stimulation by extracellular ATP is a critical determinant of epithelial cell migration and repair following injury and is associated with activation of extracellular signal-regulated kinases (ERK1/2) and matrix metalloproteinase-9 (MMP-9). Stimulation of these integral features of epithelial cell migration and repair processes was found to require the activation of Duox1. Our findings demonstrate a novel role for Duox1 in the tracheobronchial epithelium, in addition to its proposed role in antimicrobial host defense, by participating in epithelial repair processes to maintain epithelial integrity and barrier function in the face of environmental stress.

Received for publication July 10, 2006. Revision received November 14, 2006.

* This work was supported in part by grants from the NHLBI, National Institutes of Health (HL068865 and HL074295), a training grant from the National Institute for Environmental Health Sciences (T32ES07122), and an intramural grant from the University of Vermont College of Medicine. 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.

1 These authors contributed equally to this work.

2 To whom correspondence should be addressed: Dept. of Pathology, D205 Given Bldg., 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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