Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin decrease mucosal PGE(2) content by inhibiting cyclooxygenase (COX) activity and produce damage in the small intestine. The development of intestinal lesions induced by indomethacin was accompanied by increases in intestinal motility, enterobacterial invasion, and myeloperoxidase (MPO) as well as inducible nitric oxide synthase (iNOS) activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither SC-560, a selective COX-1 inhibitor, nor rofecoxib, a selective COX-2 inhibitor, alone caused intestinal damage, but their combined administration provoked lesions in the small intestine. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and the expression of COX-2 as well as iNOS mRNA, yet the iNOS and MPO activity was increased only when rofecoxib was administered together with SC-560. Although SC-560 inhibited PG production, the level of PGE(2) recovered in a rofecoxib-dependent manner. The intestinal hypermotility in response to indomethacin was prevented by both 16,16-dimethyl PGE(2) and atropine but not by ampicillin, yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 as well as the iNOS activity in the intestinal mucosa following indomethacin treatment, thereby preventing the intestinal damage. These results suggest that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion and iNOS expression, up-regulates the expression of COX-2, and the PGE(2) derived from COX-2 counteracts the deleterious events caused by COX-1 inhibition and maintains mucosal integrity. These sequences of events explain why intestinal damage occurs when both COX-1 and COX-2 are inhibited. (C) 2010 Elsevier B.V. All rights reserved.

非甾体抗炎药（NSAIDs）如吲哚美辛通过抑制环氧化酶（COX）活性降低黏膜前列腺素E₂（PGE₂）含量，并对小肠造成损伤。吲哚美辛诱导的肠道损伤的发生伴随着肠道蠕动增加、肠细菌入侵、髓过氧化物酶（MPO）以及诱导型一氧化氮合酶（iNOS）活性升高，同时COX - 2和iNOS mRNA表达上调。选择性COX - 1抑制剂SC - 560和选择性COX - 2抑制剂罗非昔布单独使用均不会引起肠道损伤，但两者联合使用会导致小肠损伤。SC - 560会引起肠道蠕动亢进、细菌入侵以及COX - 2和iNOS mRNA表达，但只有当罗非昔布与SC - 560一起使用时，iNOS和MPO活性才会增加。尽管SC - 560抑制前列腺素生成，但PGE₂水平以依赖罗非昔布的方式恢复。16,16 - 二甲基PGE₂和阿托品可阻止吲哚美辛引起的肠道蠕动亢进，但氨苄西林不能，然而所有这些药物不仅抑制细菌入侵，还抑制吲哚美辛治疗后肠道黏膜中COX - 2的表达以及iNOS活性，从而防止肠道损伤。这些结果表明，COX - 1的抑制尽管会引起肠道蠕动亢进、细菌入侵和iNOS表达，但会上调COX - 2的表达，并且源自COX - 2的PGE₂抵消由COX - 1抑制引起的有害事件并维持黏膜完整性。这些事件顺序解释了为什么当COX - 1和COX - 2都被抑制时会发生肠道损伤。（C）2010爱思唯尔有限公司。保留所有权利。