COX inhibition and NSAID-induced gastric damage--roles in various pathogenic events.
COX inhibition and NSAID-induced gastric damage--roles in various pathogenic events.
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DOI：
10.2174/1568026054201668
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发表时间：
2005-05
影响因子：
3.4
通讯作者：
K. Takeuchi;A. Tanaka;Y. Hayashi;A. Yokota
中科院分区：
文献类型：
--
作者：
K. Takeuchi;A. Tanaka;Y. Hayashi;A. Yokota
本文综述了近年来非甾体抗炎药引起胃损伤的研究进展，重点介绍了COX抑制与致病事件的关系。传统的非甾体抗炎药，如吲哚美辛，在抑制PG生成的剂量下，增强胃动力，导致粘膜通透性和MPO活性增加，最终导致胃病变。这些病变的发展可以通过给予PGE2或抗分泌药物来预防，也可以通过与任何抗分泌作用无关的阿托品敏感机制来预防。选择性COX-2抑制剂rofecoxib对PG的产生没有影响，也不会引起胃损伤。选择性COX-1抑制剂SC-560也不会造成损伤，尽管会引起PGE2水平的降低。然而，SC-560和罗非昔布联合给药会引起胃病变的形成。SC-560，而非罗非昔布，会导致胃运动亢进和粘膜通透性增加，尽管MPO活性水平仅在罗非昔布联合给药时才会增加。给药SC-560和吲哚美辛后胃中有COX-2 mRNA表达，而罗非昔布不表达。抑制胃运动亢进剂量的阿托品可阻止吲哚美辛引起的COX-2表达上调，而抗分泌剂量的奥美拉唑则不能。我们得出结论，非甾体抗炎药的胃溃疡特性不仅仅是由抑制COX-1引起的，还需要同时抑制COX-1和COX-2， COX-1的抑制上调COX-2的表达，与胃运动亢进有关，COX-2产生的pg抵消了COX-1抑制的有害影响。
This article reviews our recent studies on NSAID-induced gastric damage, focusing on the relation between COX inhibition and pathogenic events. Conventional NSAIDs such as indomethacin, at a dose that inhibits PG production, enhance gastric motility, resulting in an increase in mucosal permeability and MPO activity, and eventually, gastric lesions. The development of these lesions can be prevented by administering PGE2 or antisecretory drugs, and also via an atropine-sensitive mechanism, not related to any antisecretory action. The selective COX-2 inhibitor rofecoxib has no effect on PG production and does not induce damage in the stomach. The selective COX-1 inhibitor SC-560 also does not cause damage, despite evoking a decrease in the PGE2 level. The combined administration of SC-560 and rofecoxib, however, provokes the formation of gastric lesions. SC-560, but not rofecoxib, causes gastric hypermotility and an increase in mucosal permeability, although the level of MPO activity increases only when rofecoxib is co-administered. COX-2 mRNA is expressed in the stomach after administration of SC-560 and indomethacin but not rofecoxib. The up-regulation of COX-2 expression in response to indomethacin is prevented by atropine at a dose that inhibits gastric hypermotility but not by omeprazole at an antisecretory dose. We conclude that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by the inhibition of COX-1 and require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 up-regulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition.