Roles of endogenous prostaglandins and cyclooxygenase isozymes in healing of indomethacin-induced small intestinal lesions in rats
Roles of endogenous prostaglandins and cyclooxygenase isozymes in healing of indomethacin-induced small intestinal lesions in rats
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DOI：
10.1124/jpet.106.103994
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发表时间：
2006-08-01
影响因子：
3.5
通讯作者：
Takeuchi, Koji
中科院分区：
文献类型：
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作者：
Hatazawa, Ryo;Ohno, Ryoko;Takeuchi, Koji
探讨前列腺素(PGs)/环氧合酶(COX)在消炎痛诱导的大鼠小肠溃疡愈合中的作用。给动物注射消炎痛(10 mg/kg，皮下注射)。并在1、2、3、5和7天后被杀。给予消炎痛(2 mg/kg)、5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole(SC560；COX-1抑制剂，3 mg/kg)和罗非昔布(COX-2抑制剂，3 mg/kg)。每日一次，连续6天，在试验期的前3天或最后3天。所有服用6天的COX抑制剂均显著影响这些溃疡的愈合。前3天服用罗非昔布或后3天服用SC560也会影响愈合。COX-2mRNA在胃溃疡后表达上调，持续3d后消失。胃黏膜PGE(2)含量在溃疡后3h内下降，24 h后恢复正常，3d后高于正常水平。罗非昔布可降低溃疡后4d的PGE(2)含量，但对SC560无影响，而对7d的PGE(2)含量无影响。当COX抑制剂影响愈合时，溃疡粘膜中的血管含量减少。前列环素E受体(EP)4拮抗剂可模拟吲哚美辛对愈合的不利影响，PGE(2)和EP4激动剂联合应用可逆转其作用。综上所述，内源性前列腺素通过EP4受体在肠溃疡的愈合中发挥作用，但不同的愈合阶段所涉及的COX同工酶不同：早期的COX-2和晚期的COX-1。
The role of prostaglandins (PGs)/cyclooxygenase (COX) in the healing of indomethacin-induced small intestinal ulcers was examined in rats. Animals were given indomethacin (10 mg/kg s.c.) and killed 1, 2, 3, 5, and 7 days later. Indomethacin (2 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC560; COX-1 inhibitor; 3 mg/kg), and rofecoxib (COX-2 inhibitor; 3 mg/kg) were given p.o. once daily for 6 days, during the first 3 days or last 3 days of the experimental period. All COX inhibitors given for 6 days significantly impaired the healing of these ulcers. Healing was also impaired by rofecoxib given for the first 3 days or by SC560 given for the last 3 days. The expression of COX-2 mRNA in the intestine was up-regulated after ulceration, persisting for 3 days and dissipating thereafter. Mucosal PGE(2) contents decreased within 3 h after ulceration, recovered 24 h later, and increased above normal 1 similar to 3 days later. The PGE(2) content at 4 days after ulceration was decreased by rofecoxib but not SC560, whereas that at 7 days was suppressed by SC560 but not rofecoxib. Vascular content in the ulcerated mucosa decreased when the healing was impaired by COX inhibitors. The deleterious effect of indomethacin on healing was mimicked by a prostacyclin E receptor (EP) 4 antagonist and reversed by coadministration of PGE(2) as well as an EP4 agonist. In conclusion, endogenous PGs play a role in the healing of intestinal ulcers through EP4 receptors, yet the COX isozyme involved differs depending on the stage of healing; COX-2 in the early stage and COX-1 in the late stage.