Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
J Pharmacol Exp Ther. 2012 Jul;342(1):140-9. doi: 10.1124/jpet.111.190116. Epub 2012 Apr 10.
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.
非甾体抗炎药（NSAIDs）可损害胃溃疡愈合。本研究探讨了环氧化酶（COX）抑制剂对 NSAID 激活基因-1（NAG-1）在溃疡修复损伤中的作用。通过乙酸诱导大鼠胃溃疡。4 天后，动物每天接受腹腔内吲哚美辛（非选择性 COX-1/COX-2 抑制剂；1mg/kg）、5-（4-氯苯基）-1-（4-甲氧基苯基）-3-三氟甲基吡唑（SC-560）（选择性 COX-1 抑制剂；2.5mg/kg）、（5-二甲基-3-（3-氟苯基）-4-（4-甲磺酰基）苯基-2(5H)-呋喃酮（DFU）（选择性 COX-2 抑制剂；5mg/kg）、塞来昔布（选择性 COX-2 抑制剂；1mg/kg）和伐地昔布（选择性 COX-2 抑制剂；1mg/kg），连续 1、3 或 7 天。处理溃疡组织以评估：1）COX-1、COX-2、NAG-1、增殖细胞核抗原（PCNA）和活化的 caspase-3 表达；2）溃疡面积；和 3）前列腺素 E（2）（PGE（2））水平。溃疡组织中 COX-1 的表达减少，而 COX-2 的表达增强。吲哚美辛、DFU 和 SC-560 延迟了溃疡愈合，但塞来昔布和伐地昔布没有。SC-560、DFU、塞来昔布、伐地昔布和吲哚美辛降低了溃疡 PGE（2）水平。NAG-1 在溃疡组织中过度表达，并进一步增强了吲哚美辛、DFU 和 SC-560 的表达，但塞来昔布和伐地昔布没有。吲哚美辛降低了溃疡区的 PCNA 表达，但其他测试药物没有。吲哚美辛、DFU 和 SC-560 增加了溃疡中活化的 caspase-3 的表达，并进一步增强了其表达，但塞来昔布和伐地昔布没有。这些发现表明：1）COX 抑制剂对胃溃疡愈合具有不同的损害作用，其机制与 COX 同工酶和前列腺素产生的抑制无关；2）NAG-1 的诱导，随后是促凋亡途径的激活，可能有助于 COX 抑制剂对溃疡愈合的损害作用。
