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