Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease: toxins, mediators, and modulators of gene expression.

SUMMARY: : There is a growing body of both experimental and clinical evidence to suggest that chronic gut inflammation is associated with enhanced production of reactive metabolites of oxygen (e.g., superoxide, hydrogen peroxide) and nitrogen (e.g., nitric oxide). Pharmacologic intervention studies suggest that some of the tissue injury and dysfunction as well as the inflammatory process itself are mediated directly or indirectly by these oxidants and free radicals. Historically, these reactive species have been thought to promote inflammatory tissue injury via their ability to oxidize and degrade essential cellular constituents. However, more recent work suggests that oxygen-and nitrogen-derived metabolites may mediate gut pathobiology in more subtle ways. For example, nontoxic levels of superoxide- and/or nitric oxide-derived oxidants and free radicals may act as pro-inflammatory signaling agents as well as activate certain transcription factors (e.g., nuclear factor κB, activation protein [AP]-1) that are known to up-regulate the expression of a variety of different genes that are important in the inflammatory response. These data suggest that the sustained overproduction of these reactive species in the chronically inflamed gut may contribute to the pathophysiology of IBD by enhancing the production of toxins, mediators, and modulators of gene expression.