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S-Nitrosothiols Inhibit Cytokine-Mediated Induction of Matrix Metalloproteinase-9 in Airway Epithelial Cells

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California Davis School of Medicine, Davis, California; and Department of Microbiology, Kumamoto University School of Medicine, Kumamoto, Japan.

Address correspondence to: Albert van der Vliet, Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405. E-mail: Albert.van-der-Vliet{at}uvm.edu

Inflammatory lung diseases are associated with increased production of matrix metalloproteinase-9 (MMP-9) from infiltrating granulocytes or from the respiratory epithelium, and inappropriate expression and activation of MMP-9 may be associated with tissue injury and airway remodeling. Inflammatory conditions also result in increased expression of inducible nitric oxide synthase (iNOS), and nitric oxide (NO^·) has been reported to have variable effects on MMP-9 gene expression and activation in various cell types. We investigated the involvement of NO^· or its metabolites on MMP-9 expression in human bronchial and alveolar epithelial cells by studying effects of NOS inhibition or exogenous NO^· donors on cytokine-induced MMP-9 expression. Although inhibition of NOS, transfection with iNOS, or addition of NO^· donors did not affect MMP-9 induction by inflammatory cytokines, addition of S-nitrosothiols dramatically inhibited MMP-9 expression, which was potentiated by depletion of cellular GSH. Cytokine-induced MMP-9 expression involves the activation of the transcription factor NF-B, and S-nitrosothiols, in contrast to NO^·, were found to inhibit cytokine-induced nuclear translocation and DNA binding of NF-B. The inhibitory effects of S-nitrosothiols on cytokine-induced lung epithelial MMP-9 expression illustrate an additional mechanism by which nitrosative stress may affect epithelial injury and repair processes during conditions of airway inflammation.

Abbreviations: activator protein-1, AP-1 • bronchoalveolar lavage fluids, BALF • bovine serum albumin, BSA • L-buthionine-[S,R]-sulfoximine, BSO • colony-forming units, CFU • chronic obstructive pulmonary disease, COPD • diethylenetriamine NONOate, DETA NONOate • enhanced chemiluminescence, ECL • electrophoretic mobility shift assay, EMSA • fetal bovine serum, FBS • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • S-nitrosoglutathione, GSNO • interferon , IFN • immunoglobulin G, IgG • inhibitor of NF-B, IB • interleukin-1ß, IL-1ß • inducible nitric oxide synthase, iNOS • N^G-monomethyl-L-arginine, L-NMMA • lipopolysaccharide, LPS • matrix metalloproteinase, MMP • nuclear factor-kappa B, NF-B • primary normal human bronchial epithelial cells, NHBE • nitric oxide, NO^· • phosphate-buffered saline, PBS • proform of MMP, proMMP • reactive nitrogen species, RNS • reverse transcription-polymerase chain reaction, RT-PCR • 3-morpholinosydnonimine, SIN-1 • S-nitroso-N-acetyl-[D,L]-penicillamine, SNAP • tumor necrosis factor , TNF-

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