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

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-kappaB, and S-nitrosothiols, in contrast to NO(.), were found to inhibit cytokine-induced nuclear translocation and DNA binding of NF-kappaB. 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.