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Peroxynitrite and inflammatory bowel disease

Idiopathic inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which lead an unpredictable clinical course undergoing a succession of exacerbations and remissions of variable intensity. The highest incidence rates for IBD are found in developed countries of the northern hemisphere (UK, Scandinavia, Canada, USA) with the average annual incidence ranging from six to 13 new cases per year per 100 000 of the general population.1 For the patient, the consequences of IBD include rectal bleeding, diarrhoea, weight loss, and a reduced quality of life and may even result in death (mortality rate for UK, USA, Canada, Scandinavia ∼3.9 per 106 per year (combined statistics from 1950 to 19942)).

Investigators working on the aetiology of IBD have proposed many factors which are thought to be involved in the initiation or exacerbation, or both, of the inflammatory process. Some of these factors include increased epithelial permeability, inappropriate neutrophil infiltration into the intestine, activation of mast cells, and increased concentrations of pro-inflammatory mediators (cytokines, leukotrienes, reactive oxygen metabolites (ROMs)). In addition, over the past 10 years, the overproduction of nitric oxide (NO•) has received considerable attention as an important player in the pathogenesis of IBD.3-5 NO•is a free radical produced from l-arginine via the enzyme nitric oxide synthase (NOS). Alone, NO• is a weak free radical; however, it can react with superoxide (O2 −•) to produce peroxynitrite (OONO−) a highly toxic reactive nitrogen intermediary. In 1990, Beckman and colleagues6 showed that peroxynitrite had hydroxyl radical (•OH)-like activity at physiological pH and proposed a pathophysiological role for peroxynitrite. This work has since generated substantial interest in the role of peroxynitrite in IBD as it may provide an explanation for pathological roles …