PT  - JOURNAL ARTICLE
AU  - Colucci, Rocchina
AU  - Antonioli, Luca
AU  - Bernardini, Nunzia
AU  - Ippolito, Chiara
AU  - Segnani, Cristina
AU  - Awwad, Oriana
AU  - Tuccori, Marco
AU  - Blandizzi, Corrado
AU  - Scarpignato, Carmelo
AU  - Fornai, Matteo
TI  - Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing
AID  - 10.1124/jpet.111.190116
DP  - 2012 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 140--149
VI  - 342
IP  - 1
4099  - http://jpet.aspetjournals.org/content/342/1/140.short
4100  - http://jpet.aspetjournals.org/content/342/1/140.full
SO  - J Pharmacol Exp Ther2012 Jul 01; 342
AB  - Nonsteroidal 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 (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (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; and 3) prostaglandin E2 (PGE2) levels. COX-1 expression in ulcerated tissues was decreased, whereas 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 overexpressed 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 the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and 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; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.