NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2
NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2
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DOI：
10.1053/gast.2000.16510
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发表时间：
2000-09-01
期刊：
影响因子：
29.4
通讯作者：
Vergnolle, N
中科院分区：
文献类型：
--
作者：
Wallace, JL;McKnight, W;Vergnolle, N
背景与目的：选择性环氧合酶 (COX)-2 抑制剂比传统非甾体抗炎药 (NSAID) 产生的胃损伤更小，表明 NSAID 通过抑制 COX-1 造成胃损伤。我们通过使用选择性 COX-1 抑制剂 (SC-560) 在大鼠中测试了这一假设。方法：确定 SC-560、塞来昔布（选择性 COX-2 抑制剂）或两种抑制剂的组合对胃损伤和前列腺素合成的影响。在角叉菜胶气囊模型中评估了药物对 COX-1 与 COX-2 的选择性。还评估了 COX-1 优先抑制剂酮咯酸。评估了这些抑制剂对白细胞粘附血管内皮和胃血流量的影响，结果：SC-560 显着降低胃前列腺素合成和血小板 COX-1 活性，但不影响 COX-2，并且不会引起胃损伤。塞来昔布不影响胃前列腺素E-2合成，也不引起胃损伤。然而，SC-560 和塞来考昔的组合总是会导致出血性糜烂形成，与吲哚美辛所见的情况相当，酮咯酸仅在抑制两种 COX 亚型的剂量下或与 COX-2 抑制剂一起使用时才会造成损伤。塞来昔布（而非 SC-560）显着增加了白细胞粘附性，而 SC-560（而非塞来昔布）减少了胃血流量。结论：NSAID 引起的大鼠胃损伤需要同时抑制 COX-1 和 COX-2。
Background & Aims: Selective cyclooxygenase (COX)-2 inhibitors produce less gastric damage than conventional nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting that NSAIDs cause damage by inhibiting COX-1. We tested this hypothesis in rats by using a selective COX-1 inhibitor (SC-560). Methods: The effects of SC-560, celecoxib (selective COX-2 inhibitor), or a combination of both inhibitors on gastric damage and prostaglandin synthesis were determined. Selectivity of the drugs for COX-1 vs. COX-2 was assessed in the carrageenan-airpouch model. A COX-1-preferential inhibitor, ketorolac, was also evaluated. The effects of these inhibitors on leukocyte adherence to vascular endothelium and on gastric blood flow were assessed, Results: SC-560 markedly reduced gastric prostaglandin synthesis and platelet COX-1 activity, but spared COX-2 and did not cause gastric damage. Celecoxib did not affect gastric prostaglandin E-2 synthesis and did not cause gastric damage. However, the combination of SC-560 and celecoxib invariably caused hemorrhagic erosion formation, comparable to that seen with indomethacin, Ketorolac caused damage only at doses that inhibited both COX isoforms, or when given with a COX-2 inhibitor. Celecoxib, but not SC-560, significantly increased leukocyte adherence, whereas SC-560, but not celecoxib, reduced gastric blood flow. Conclusions: Inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.