Tanaka Akiko, Hase Shoko, Miyazawa Tohru, Ohno Ryoko, Takeuchi Koji
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
J Pharmacol Exp Ther. 2002 Dec;303(3):1248-54. doi: 10.1124/jpet.102.041715.
We recently reported that cyclooxygenase (COX)-2 expression was up-regulated in the rat small intestine after administration of indomethacin, and this may be a key to nonsteroidal anti-inflammatory drug (NSAID)-induced intestinal damage. In the present study, we investigated the effect of inhibiting COX-1 or COX-2 on various intestinal events occurring in association with NSAID-induced intestinal damage. Rats without fasting were treated with indomethacin, SC-560 (a selective COX-1 inhibitor), rofecoxib (a selective COX-2 inhibitor), or SC-560 plus rofecoxib, and the following parameters were examined in the small intestine: the lesion score, the enterobacterial number, myeloperoxidase (MPO) and inducible nitric-oxide synthase (iNOS) activity, and intestinal motility. Indomethacin decreased mucosal prostaglandin (PG)E2 content and caused damage in the intestine within 24 h, accompanied by an increase in intestinal contractility, bacterial numbers, and MPO as well as iNOS activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither SC-560 nor rofecoxib alone caused intestinal damage, but their combined administration produced lesions. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion, and COX-2 as well as iNOS mRNA expression, yet the iNOS and MPO activity was increased only when rofecoxib was also administered. Although SC-560 inhibited the PG production, the level of PGE2 was restored 6 h later, in a rofecoxib-dependent manner. We conclude that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion, and iNOS expression, up-regulates the expression of COX-2, and the PGE2 produced by COX-2 counteracts deleterious events, and maintains the mucosal integrity. This sequence of events explains why intestinal damage occurs only when both COX-1 and COX-2 are inhibited.
我们最近报道，给予吲哚美辛后，大鼠小肠中环氧化酶（COX）-2的表达上调，这可能是非甾体抗炎药（NSAID）诱导肠道损伤的关键。在本研究中，我们研究了抑制COX-1或COX-2对与NSAID诱导的肠道损伤相关的各种肠道事件的影响。对未禁食的大鼠给予吲哚美辛、SC-560（一种选择性COX-1抑制剂）、罗非昔布（一种选择性COX-2抑制剂）或SC-560加罗非昔布，并检测小肠中的以下参数：损伤评分、肠细菌数量、髓过氧化物酶（MPO）和诱导型一氧化氮合酶（iNOS）活性以及肠道运动性。吲哚美辛降低了黏膜前列腺素（PG）E2含量，并在24小时内导致肠道损伤，同时伴有肠道收缩性、细菌数量、MPO以及iNOS活性增加，以及COX-2和iNOS mRNA表达上调。单独使用SC-560或罗非昔布均未引起肠道损伤，但联合给药则产生了损伤。SC-560而非罗非昔布导致肠道运动亢进、细菌侵袭以及COX-2和iNOS mRNA表达，但仅在同时给予罗非昔布时iNOS和MPO活性才增加。尽管SC-560抑制了PG生成，但6小时后PGE2水平以罗非昔布依赖的方式恢复。我们得出结论，抑制COX-1尽管会导致肠道运动亢进、细菌侵袭和iNOS表达，但会上调COX-2的表达，且COX-2产生的PGE2可抵消有害事件并维持黏膜完整性。这一系列事件解释了为何仅在COX-1和COX-2均被抑制时才会发生肠道损伤。
