Role of the proteasome in rat indomethacin-induced gastropathy

S. J. Brand, Z. Morise, S. Tagerud, L. Mazzola, D. N. Granger, M. B. Grisham

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Background and Aims: Intercellular adhesion molecule (ICAM)-dependent adhesion of circulating neutrophils to microvascular endothelial cells is thought to be critical in causing indomethacin (nonsteroidal antiinflammatory drug [NSAID])-induced gastropathy. Indomethacin stimulates tumor necrosis factor (TNF)-α expression, which may enhance adhesiveness of gastric capillaries for neutrophils by activating ICAM expression on endothelial cells. Stimulation of ICAM expression is mediated by activation of the transcription factor NF-κB. Because activation of NF-κB requires proteolytic degradation of IκB by the ubiquitin-proteasome pathway of intracellular proteolysis, treatment with proteasome inhibitors was evaluated for efficacy in preventing NSAID gastropathy. Methods: The effect of proteasome inhibitors on gastric injury caused by oral indomethacin was measured, along with their effects on gastric mucosal permeability measured by the blood to lumen EDTA clearance. Gastric ICAM expression was measured in vivo using infusion of a labeled rat ICAM antibody. Results: Proteasome inhibitors prevented NSAID gastropathy if administered from 0 to 12 hours before indomethacin. Equivalent efficacy was observed with intravenous and oral administration of proteasome inhibitors. There was a strong correlation between the potency of proteasome inhibitors in preventing NSAID gastropathy and their potency in inhibiting intracellular proteolysis or their anti- inflammatory potency. All three classes of proteasome inhibitors, peptide boronates, aldehydes, and the mechanistically different lactacystin, prevented NSAID gastropathy. Proteasome inhibitor treatment also abolished the increase in gastric mucosal permeability and the increase in gastric endothelial ICAM expression induced by indomethacin. Conclusions: Indomethacin-induced gastric injury and increased ICAM expression are inhibited by inhibition of the proteasome.

Original languageEnglish
Pages (from-to)865-873
Number of pages9
JournalGastroenterology
Volume116
Issue number4
DOIs
Publication statusPublished - 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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