INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA AND APOPTOSIS IN GASTRIC-MUCOSAL INJURY BY INDOMETHACIN - EFFECT OF OMEPRAZOLE AND EBROTIDINE

Background: The gastric injury associated with nonsteroidal anti-infla mmatory drug (NSAID) therapy has been linked to the detrimental effect s of the agents on the processes of prostaglandin generation, leukocyt e adherence, superoxides production, and mucosal cell proliferation. I n the present study we investigated the expression of tumor necrosis f actor-alpha (TNF-alpha) and epithelial cell apoptosis during indometha cin-induced gastric mucosal injury and evaluated the effect of two ant iulcer agents on this process. Methods: The experiments were carried o ut with groups of rats subjected to intragastric pretreatment with 40 mg/kg omeprazole, 100 mg/kg ebrotidine, or vehicle, followed 30 min la ter by an intragastric dose of indomethacin at 60 mg/kg. After 2 h the animals were killed, and the gastric mucosal tissue used for macrosco pic damage assessment, quantitation of TNF-alpha expression, and the a ssay of epithelial cell apoptosis. Results: In the absence of antiulce r drugs, indomethacin caused extensive multiple hemorrhagic lesions ac companied by a 47% increase in mucosal expression of TNF-alpha and a d ramatic (>300-fold) enhancement in gastric epithelial cell apoptosis. Pretreatment with a proton pump inhibitor, omeprazole, produced only m arginal (6-8%) reduction in the extent of mucosal damage caused by ind omethacin, whereas the mucosal expression of TNF-alpha decreased by 15 % and the apoptotic DNA fragmentation by 10-13%. In contrast, the H-2- receptor antagonist ebrotidine, also known for its gastroprotective ef fects, not only successfully prevented (98.3%) the enhancement in muco sal TNF-alpha expression caused by indomethacin but also caused a 54% reduction in the epithelial cell apoptosis. These effects of ebrotidin e were, furthermore, reflected in a 90.2% prevention in the gastric mu cosal damage. Conclusions: Our findings provide new insights into the mechanism of gastric injury caused by NSAIDs and show that ebrotidine protection against indomethacin-induced mucosal damage occurs through the inhibition of epithelial cell apoptosis triggered by the enhanceme nt in the mucosal TNF-alpha expression. Our data also show that omepra zole does not possess antiapoptotic properties.