The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice

NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes

“…Second, in studies by our laboratory and others it has been demonstrated that COX-1 knockout mice do not have ulcer disease (as would be predicted by Vane's concept), whereas the mice readily undergo gastrointestinal ulceration and bleeding when challenged with aspirin and other non-selective NSAIDs (Langenbach et al 1995;Darling et al 2004). Also, in a recent paper, we demonstrated that in COX knockout mice there is a statistical association between aspirin's ability to reduce surface hydrophobicity and induce gastric injury, whereas there was no such association between aspirin's ability to affect gastric mucosal prostaglandin concentration and the development of stomach haemorrhagic lesions (Darling et al 2004). Lastly, the preclinical and clinical evidence that COX-1 selective inhibitors are not injurious to the gastrointestinal tract and that both COX isoforms need to be blocked for mucosal damage to occur has made investigators reassess the entire concept originally proposed by Vane (Wallace et al 2000).…”

“…First, a number of in-vivo and in-vitro studies have demonstrated that the gastrointestinal injurious potential of a number of NSAIDs can be dissociated in time, dose and route of administration from their ability to inhibit COX-1 (Whittle 1981;Ligumsky et al 1982Ligumsky et al , 1983Ligumsky et al , 1990. Second, in studies by our laboratory and others it has been demonstrated that COX-1 knockout mice do not have ulcer disease (as would be predicted by Vane's concept), whereas the mice readily undergo gastrointestinal ulceration and bleeding when challenged with aspirin and other non-selective NSAIDs (Langenbach et al 1995;Darling et al 2004). Also, in a recent paper, we demonstrated that in COX knockout mice there is a statistical association between aspirin's ability to reduce surface hydrophobicity and induce gastric injury, whereas there was no such association between aspirin's ability to affect gastric mucosal prostaglandin concentration and the development of stomach haemorrhagic lesions (Darling et al 2004).…”

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“…It is an important barrier against self-digestion and acts as an antioxidant, scavenging free radicals in the mucosa 35 . Ulcerogenic substances cause disruptions in this barrier and permit contact between the gastric juice and epithelial cells, leading to mucosal damage 36 . Thus, the increased stimulation of mucus production by 1.46-fold over the control group is a relevant part of the mechanism of gastric mucosal protection by EMA.…”

Physiological Significance of Lysophospholipids that Act on the Lumen Side of Mammalian Lower Digestive Tracts

“…42) Furthermore, PC prevented gastrointestinal mucosal injury induced by acetic acid, 43) bile acid, 44) trinitrobenzene sulfonic acid 45) and aspirin. 46) Patients with ulcerative colitis had lower concentrations of PC and LPC in the rectal mucus than patients with Crohn's disease and control subjects, 47) and oral administration of PC in a delayed release mode was beneficial for chronic ulcerative colitis. 47,48) PC in the mucus has an anti-inflammatory effect, and the mucus layer of patients with ulcerative colitis was characterized by a low level of PC.…”