Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors

By far the most attention has been paid to the deleterious actions of nonsteroidal anti-inflammatory drugs (NSAIDs), including isoform selective agents that inhibit cyclooxygenase (COX), on the upper gastrointestinal tract, particularly the gastric and duodenal mucosa. However, recent studies confirm a relatively high incidence of serious clinical events, especially with the more-established drugs of this class, involving the small intestine. Pathogenic factors that have been proposed from early studies in such enteropathy have included the enterohepatic circulation of the nonsteroidal anti-inflammatory drugs, inhibition of cyclooxygenase, surface epithelial changes and focal microvascular events. More recent work has concerned the role of infiltrating inflammatory cells, the relative roles of cyclooxygenase isoforms, COX-1 and COX-2 and the key involvement of inducible nitric oxide (NO) synthase and its product in combination with superoxide, peroxynitrite. In the present review, evidence for the underlying involvement of each these processes, and their sequential integration in the development of the intestinal injury and ulceration promoted by nonsteroidal anti-inflammatory drugs has been considered. (C) 2004 Elsevier B.V. All rights reserved.