Non-steroidal anti-inflammatory drug-induced gastric damage in experimental animals: underlying pathological mechanisms.

A major impetus to experimental studies examining the pathogenesis of NSAID-induced gastric damage is the hope that key mechanisms can be identified that may lead to the design of "safer" NSAIDs or to the development of novel cytoprotectives to co-administer with current NSAIDs. Virtually every hypothesis proposed to explain the pathogenesis of NSAID-induced gastric damage has arisen from studies examining fundic lesions. Our results suggest that not only is the pathogenesis of gastric damage in the fundus and antrum of the rat potentially very different but that it is NSAID-induced damage to the rat gastric antrum (and not the fundus) that more closely resembles that of humans. Thus, hypotheses constructed from experimental studies examining fundic damage may not be predictive of the clinical setting. We would suggest, therefore, that future studies should concentrate on studying the pathogenesis of antral ulceration induced by NSAIDs. In particular, we believe that future research should assess whether NSAIDs do indeed reduce blood flow in the gastric antrum and define the mechanism(s) involved. Identification of these processes should significantly advance our understanding of antral ulceration and may suggest novel approaches in the design of cytoprotective agents. Recent work has established that two distinct forms of the enzyme cyclooxygenase (COX) can catalyse the metabolism of arachidonic acid and initiate prostaglandin synthesis. It is hypothesised (De Witt et al., 1993) that the analgesic/anti-inflammatory effect of current NSAIDs is achieved through inhibition of COX 2, whereas their side effects (such as antral ulceration) result as a consequence of inhibition of gastric COX 1. The recently described selective inhibitor of COX 2, NS398, has been shown to be analgesic and anti-inflammatory without causing gastric ulceration (Futaki et al., 1993; Masferrer et al., 1994). If key mechanisms (such as alterations in blood flow) of NSAID-induced antral damage can be identified, then it would be hypothesised that selective inhibitors of COX 1 would be ulcerogenic and reduce antral blood flow, whereas inhibitors of COX 2 would not share either of these properties. If this hypothesis can be substantiated, then inhibitors of COX 2 may be the next generation of "gastric safe" NSAIDs.