NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND INFLAMMATORY BOWEL DISEASE: CURRENT PERSPECTIVES

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Abstract

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-κB and/or peroxisome proliferator-activated receptors γ. 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-κB 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.

Section snippets

BACKGROUND

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed drugs because of their anti-inflammatory and analgesic properties. However, their use is associated with an elevated risk of damage to the gastrointestinal mucosa and related complications 1., 2., 3., 4.. Henry et al. [5] studied the relative risk of gastrointestinal complications using a meta-analytical approach: the meta-analysis showed wide differences among individual drugs, although some of the differences may be

MECHANISMS LEADING TO INTESTINAL DAMAGE

An enteropathy can be detected in 20–60% of NSAIDs recipients, depending on the method used for the diagnosis 14., 15.. Although most of the clinical evidence on the intestinal adverse effects of NSAIDs comes from case reports [16], several experimental studies in animals allowed to put forward different hypotheses to explain the possible mechanisms of enteric toxicity.

COX INHIBITORS AND IBD

Animal models of IBD support the contention that eicosanoids are involved in modulating tissue inflammation [47], but the studies on the impact of COX-2 inhibition on animal models of colitis are widely dissonant (Table II). In accordance with the central role of eicosanoids in maintaining the inflammatory process, Karmeli et al. [48] demonstrated that COX-2 inhibitors have a beneficial effect on experimental colitis in rats, acting by reducing colonic eicosanoids generation. In contrast,

CURRENT PERSPECTIVES

An aspect that is often overlooked is that every NSAID (whether or not it is a selective COX-2 inhibitor) is endowed with a range of pharmacological activities that may lead to significant differences in the effects of an individual agent on the inflamed mucosa. For instance, the salicylic acid derivative 5-ASA is widely used in the treatment of IBD, and its anti-inflammatory action is due to inhibition of activation of transcription factor NF-κB [13].

NF-κB designates a group of transcription

CONCLUSIONS

From the preceding paragraphs, it emerges that the mechanisms leading to intestinal damage by NSAIDs are different from those underlying the gastric damage. Moreover, the two different isoforms of COX seem to play different roles in maintaining homeostasis of gastrointestinal mucosa and in the process of gastrointestinal ulcer healing.

The impact of COX-2 selective inhibitors on IBD is currently controversial: on one hand, COX inhibition is fundamental for the modulation of the inflammatory

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