title: Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing.
abstract: 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 E(2) (PGE(2)) 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 PGE(2) 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.
authors.affiliation: Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.forename: Nunzia
authors.initials: N
authors.lastname: Bernardini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ippolito
authors.forename: Cristina
authors.initials: C
authors.lastname: Segnani
authors.forename: Oriana
authors.initials: O
authors.lastname: Awwad
authors.forename: Marco
authors.initials: M
authors.lastname: Tuccori
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Carmelo
authors.initials: C
authors.lastname: Scarpignato
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; C526142:Gdf15 protein, rat; D055436:Growth Differentiation Factor 15; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; D053148:Caspase 3; D015232:Dinoprostone