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Dig Liver Dis. 2001 Dec;33 Suppl 2:S35-43.

Mechanism of non-steroidal anti-inflammatory drug-gastropathy.

Author information

1
University of Perugia, Italy. fiorucci@unipg.it

Abstract

Non-steroidal anti-inflammatory drugs are recognized to cause gastrointestinal damage impairing the defense ability of gastric mucosal barrier. A variety of mechanisms due to non-steroidal anti-inflammatory drugs direct irritant (topical) action and to their main pharmacological (systemic) effect, is involved in the pathogenesis of non-steroidal anti-inflammatory drugs induced gastropathy. The systemic activity comprises the inhibition of cyclo-oxygenase, but an increasing body of evidence suggests that cyclo-oxygenase-independent mechanisms are involved in the development of gastric injury. In line with this concept, neither cyclo-oxygenase-1 nor cyclo-oxygenase-2 deficient mice develop spontaneous gastrointestinal ulcers and pharmacological inhibition of cyclo-oxygenase-1 or cyclo-oxygenase-2 with selective inhibitors doesn't elicit gastrointestinal damage; suggesting that both isoforms of cyclo-oxygenase enzymes have to be inhibited to induce ulcers. Moreover non-steroidal anti-inflammatory drugs administration in rats, induces the systemic release of tumor necrosis factor-alpha and drives gastric epithelial cells to apoptosis activating the pro-apoptotic cascade of caspases. In response to non-steroidal anti-inflammatory drugs, neutrophils are recruited into the gastric microcirculation through a process that requires activation of adhesion molecules. Although there is virtually no information regarding the regulation of expression of gastric endothelial cell adhesion molecules in response to non steroidal anti-inflammatory drugs, the nuclear factor-kB may represent a potential modulator. Supporting this view, selective proteasome inhibitors inhibit nuclear translocation of nuclear factor-kB induced by tumor necrosis factor-alpha in human endothelial cells in vitro and reduce indomethacin-induced gastric mucosal injury in vivo.

PMID:
11827361
DOI:
10.1016/s1590-8658(01)80157-2
[Indexed for MEDLINE]

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