Molecular mechanisms involved in NSAID-induced gastropathy.
A growing body of experimental evidence indicates that leukocyte-endothelial cell interactions may play an important role in the pathogenesis of NSAID-induced gastropathy. Using a newly described, dual radiolabeled monoclonal antibody technique to quantify adhesion molecule surface expression in vivo, we have demonstrated increases in surface expression of ICAM-1 and P-selectin in the gastric mucosa after oral administration of indomethacin. We have also found that CD18-, ICAM-1-, or P-selectin-deficient mice are less sensitive to the ulcerogenic effects of orally administered indomethacin. Although there is virtually no information regarding the regulation of expression of endothelial cell adhesion molecules (ECAMs) in experimental NSAID-induced gastropathy, the nuclear transcription factor KB (NFKB) may represent a potential modulator of transcriptional activation of ECAM expression. We have demonstrated that two structurally distinct yet highly selective proteasome inhibitors (MG341, lactacystin) inhibit tumor necrosis factor (TNF)-induced NFKB activation as well as ECAM expression in human endothelial cells in vitro. In addition, we found that these proteasome inhibitors significantly reduced indomethacin-induced gastric mucosal injury as well as gastric mucosal ICAM-1 expression in the rat in vivo. We conclude from these studies that indomethacin activates NFKB (possibly via TNF synthesis) in gastric microvascular endothelial cells, thereby enhancing surface expression of ICAM-1 which binds the CD18 on polymorphonuclear leukocytes (PMNs). These adherent PMNs are then believed to mediate endothelial and/or epithelial cell injury either directly or indirectly.
Morise
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Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport 71130, USA.
Grisham
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MB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002448:Cell Adhesion; D007213:Indomethacin / Q000009:adverse effects*; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D013272:Stomach Diseases / Q000139:chemically induced* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin