Role of the proteasome in rat indomethacin-induced gastropathy.
OBJECTIVE
Intercellular adhesion molecule (ICAM)-dependent adhesion of circulating neutrophils to microvascular endothelial cells is thought to be critical in causing indomethacin (nonsteroidal anti-inflammatory drug [NSAID])-induced gastropathy. Indomethacin stimulates tumor necrosis factor (TNF)-alpha 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-kappaB. Because activation of NF-kappaB requires proteolytic degradation of IkappaB 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.
Brand
S J
SJ
ProScript Inc., Cambridge, Massachusetts, USA. sbrand@trlusa.com
Morise
Z
Z
Tagerud
S
S
Mazzola
L
L
Granger
D N
DN
Grisham
M B
MB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects*; D007213:Indomethacin / Q000633:toxicity*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D007213:Indomethacin