Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility
Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility
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DOI：
10.3748/wjg.v18.i18.2147
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发表时间：
2012-05-14
影响因子：
4.3
通讯作者：
Takeuchi, Koji
中科院分区：
文献类型：
--
作者：
Takeuchi, Koji
本文综述了非甾体抗炎药（NSAID）引起的胃损伤的发病机制，重点阐述了环氧合酶（COX）抑制与各种功能事件的关系。 NSAIDs，如吲哚美辛，在抑制前列腺素（PG）产生的剂量下，增强胃动力，导致粘膜通透性增加、中性粒细胞浸润和氧自由基产生，最终产生胃损伤。这些病变可以通过 PGE2 和抗分泌药物预处理来预防，也可以通过与抗分泌作用无关的阿托品敏感机制来预防。虽然单独使用罗非昔布（一种选择性 COX-2 抑制剂）和 SC-560（一种选择性 COX-1 抑制剂）不会损害胃，但这些药物联合使用会引起胃损伤。 SC-560（而非罗非昔布）会降低前列腺素 E2 (PGE2) 的产生，并导致胃动力亢进和粘膜通透性增加。给予吲哚美辛和 SC-560 后，COX-2 mRNA 在胃中表达，但罗非考昔不表达。抑制胃蠕动过度的剂量的阿托品可防止吲哚美辛诱导的 COX-2 表达上调。此外，当COX-2在各种情况下过度表达时，包括肾上腺切除术、关节炎和幽门螺杆菌感染，选择性COX-2抑制剂会对胃产生有害影响。总之，胃动力亢进在 NSAID 引起的胃损伤的发病机制中起主要作用，并且这种反应与 COX-1 抑制导致的 PG 缺乏有因果关系，发生在其他致病事件（例如粘膜通透性增加）之前。 NSAIDs 的溃疡特性需要同时抑制 COX-1 和 COX-2，抑制 COX-1 会上调与胃蠕动过度相关的 COX-2 表达，而 COX-2 产生的 PG 会抵消 COX-1 抑制的有害作用。 (C)2012年百事登。版权所有。
This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE2 and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E2 (PGE2) production and causes gastric hyperrnotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Heliobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition. (C) 2012 Baishideng. All rights reserved.