Pathogenesis of non-steroidal anti-inflammatory drug gastropathy.

Although non-steroidal anti-inflammatory drugs (NSAIDs) may impair the defensive ability of the gastric mucosal barrier through topical actions, recent evidence suggests that microcirculation disturbance plays a pivotal role in the genesis of gastric mucosal damage. In particular, attention has been drawn to the role exerted by those cytokine (TNF alpha and IL-1 beta) and adhesion molecules (LFA-1, Mac-1, ICAM-1) that regulate interactions between leukocyte and endothelial cells leading to gastric microvessels occlusion and ischaemic/hypoxic endothelial-epithelial cell damage. In recent years the role of prostaglandin synthesis inhibition in the pathogenesis of NSAID-gastropathy has been reconsidered, highlighting the immunomodulatory and pro-inflammatory consequences of prostanoids suppression. The awareness that mucosal damage is due to the non-discriminatory effect of NSAIDs on cyclo-oxygenase (COX) isoenzymes, has lead to the development of more selective, safer, COX-2 inhibitors. On the other hand, the observation that NO exerts a predominant physiological role in the maintenance of mucosal integrity has raised the opportunity to develop a new generation of NO-releasing NSAID derivatives with a reduced gastrointestinal toxicity.