Profiles of nonsteroidal anti-inflammatory drug-induced gastric antral ulcers: A comprehensive review of the preclinical data.

Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently induce gastric ulcers in the prepyloric antrum in humans; however, the mechanisms underlying this antral specificity remain unclear. Moreover, although gastric antral ulcers (AUs) exhibit poor responsiveness to histamine H2 receptor antagonists, AUs respond favorably to proton pump inhibitors (PPIs). To clarify these issues, we examined the characteristics of NSAID-induced gastric ulcers in mice. The location of gastrointestinal lesions caused by NSAIDs was entirely dependent on feeding conditions: under fasted conditions, indomethacin produced lesions selectively in the gastric corpus; under refed conditions, indomethacin induced ulcers specifically in the gastric antrum; under fed conditions, indomethacin caused ulcers only in the small intestine. Histamine H2 receptor antagonists inhibited indomethacin-induced corpus lesions in fasted mice but did not affect AUs in refed mice. In contrast, PPIs markedly inhibited the formation of both AUs and corpus lesions. The protective effects of PPIs against AUs were mediated by increasing gastric mucosal blood flow regulated via capsaicin-sensitive afferent nerves, activation of the vanilloid receptor transient receptor potential vanilloid 1, and nitric oxide synthesis. Furthermore, gastroparesis induced by restraint stress, corticotropin-releasing factor, atropine, or dopamine enhanced duodenogastric bile reflux and exacerbated indomethacin-induced AUs via 5-hydroxytryptamine-3, dopamine D2, and cholecystokinin 1 receptors. Dietary supplementation with taurocholate aggravated indomethacin-induced AUs, whereas cholestyramine, a bile acid sequestrant, attenuated them. Insoluble dietary fibers, such as cellulose, accelerated AU formation, whereas soluble fibers, such as pectin, prevented it. These findings provide new insights into the pathogenesis of NSAID-induced foregut mucosal injury and may contribute to novel and effective strategies for ulcer prevention. SIGNIFICANCE STATEMENT: Nonsteroidal anti-inflammatory drug-induced gastric ulcers are induced dependently on feeding conditions, dietary fibers, intragastric bile acids, gastric motility, and stress. This review summarizes the recent advances and provides new insights into the pathogenesis of nonsteroidal anti-inflammatory drug-induced foregut mucosal injury and may contribute to novel and effective pharmacological approaches for ulcer prevention in humans.