Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: current perspectives.
Mechanisms underlying the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively investigated, whereas those leading to intestinal damage are not completely understood. Several hypotheses have been put forward on the pathophysiology of intestinal damage by NSAIDs: enhanced intestinal permeability, inhibition of cyclooxygenase (COX), enterohepatic recirculation, and formation of adducts. The effects of COX-2 selective inhibitors, which appear to have better gastric tolerability when compared to nonselective NSAIDs, on normal and inflamed intestinal mucosa (as in Crohn's disease or ulcerative colitis) are still largely unexplored. If COX-2 inhibition plays a key role in suppressing the inflammatory process, recent evidence suggests that COX-2 products are involved in maintaining the integrity of intestinal mucosa, in the healing of gastrointestinal ulcers and in the modulation of inflammatory bowel disease (IBD). Animal models of intestinal inflammation have so far yielded conflicting results on the effects of COX-2 selective inhibitors on the intestinal mucosa. It is now clear that NSAIDs do not act through cyclooxygenase inhibition, but also have different targets such as nuclear factor-kappaB and/or peroxisome proliferator-activated receptors gamma. The peculiar pharmacological profile of each compound may help to explain the different impact of each NSAID on the inflammatory process and on IBD. Notably, the salicylic acid derivative 5-ASA is widely used in the treatment of IBD and is believed to act through nuclear factor-kappaB inhibition. Although the use of COX-2 selective inhibitors remains contraindicated in patients with IBD, studying their effects on intestinal mucosa may offer new insights into their subcellulars mechanisms of action and open new avenues for the development of novel therapies for IBD.
Cipolla
Giovanna
G
Department of Internal Medicine and Therapeutics, University of Pavia, Piazza Botta, 10, Italy.
Crema
Francesca
F
Sacco
Stefano
S
Moro
Elisabetta
E
de Ponti
Fabrizio
F
Frigo
Gianmario
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D004064:Digestive System / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors