Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAID-activated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (non-selective COX-1/COX-2 inhibitor, 1 mg/kg), SC-560 (selective COX-1 inhibitor, 2.5 mg/kg), DFU (selective COX-2 inhibitor, 5 mg/kg), celecoxib (selective COX-2 inhibitor, 1 mg/kg) and valdecoxib (selective COX-2 inhibitor, 1 mg/kg), for 1, 3 or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA) and activated caspase-3 expression; 2) ulcer area; 3) prostaglandin E₂. COX-1 expression in ulcerated tissues was decreased, while COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE₂ levels were decreased by SC-560, DFU, celecoxib, valdecoxib and indomethacin. NAG-1 was over-expressed in ulcerated tissues, and further enhanced by indomethacin, DFU and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by other test drugs. The expression of activated caspase-3 in ulcers was increased, and enhanced further by indomethacin, DFU or SC-560, but not by celecoxib or valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing