Mechanism of non-steroidal anti-inflammatory drug-gastropathy.
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.
Fiorucci
S
S
University of Perugia, Italy. fiorucci@unipg.it
Antonelli
E
E
Morelli
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004847:Epithelial Cells / Q000187:drug effects; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D010437:Peptic Ulcer / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010438:Peptic Ulcer Hemorrhage / Q000139:chemically induced; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat