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Published ahead of print on September 15, 2006, doi:10.1165/rcmb.2006-0253SM

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 2, February 2007, 138-146

A more recent version of this article appeared on February 1, 2007
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Submitted on July 12, 2006
Revised on September 12, 2006

Nitric Oxide Promotes Airway Epithelial Wound Repair through Enhanced Activation of MMP-9

Peter F Bove1, Umadevi V Wesley1, Anne-Katrin Greul1, Milena Hristova1, Wolfgang R Dostmann1, and Albert van der Vliet1*

1 Departments of Pathology, Microbiology and Molecular Genetics, and Pharmacology, University of Vermont, College of Medicine, Burlington, Vermont, USA

* To whom correspondence should be addressed. E-mail: Albert.van-der-Vliet{at}uvm.edu.

The airway epithelium provides a protective barrier against inhaled environmental toxins and microorganisms, and epithelial injury initiates a number of processes to restore its barrier integrity, including activation of matrix metalloproteinases such as MMP-9 (92-kD gelatinase B). Airway epithelial cells continuously produce nitric oxide (NO), which has been linked to cell migration and MMP-9 regulation in several cell types, but the importance of epithelial NO in mediating airway epithelial repair or MMP-9 activation is unknown. Using primary or immortalized human bronchial epithelial cells, we demonstrate that low concentrations of NO promote epithelial cell migration and wound repair in an in vitro wound assay, which was associated with increased localized expression and activation of MMP-9. In addition, in HBE1 cells that were stably transfected with inducible NOS (NOS2), to mimic constitutive epithelial NOS2 expression in vivo, NOS inhibition decreased epithelial wound repair and MMP-9 expression. The stimulatory effects of NO on epithelial wound repair and MMP-9 expression were dependent on cGMP-mediated pathways and were inhibited by 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase. Inhibition of cGMP-dependent protein kinase (PKG) attenuated NO-mediated epithelial wound closure but did not affect MMP-9 expression. However, pharmacological MMP inhibition and siRNA knockdown of MMP-9 expression demonstrated the contribution of MMP-9 to NO-mediated wound closure. Overall, our results demonstrate that NOS2-derived NO contributes to airway epithelial repair by both PKG-dependent and -independent mechanisms, and involves NO-dependent expression and activation of MMP-9.




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