Factors involved in upregulation of inducible nitric oxide synthase in rat small intestine following administration of nonsteroidal anti-inflammatory drugs
Factors involved in upregulation of inducible nitric oxide synthase in rat small intestine following administration of nonsteroidal anti-inflammatory drugs
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DOI：
10.1007/s10620-006-8045-4
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发表时间：
2006-07-01
影响因子：
3.1
通讯作者：
Takahira, Yuka
中科院分区：
文献类型：
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作者：
Takeuchi, Koji;Yokota, Aya;Takahira, Yuka
我们研究了诱导型一氧化氮（NO）合酶（iNOS）的表达在大鼠小肠后，非甾体类抗炎药（NSAID）的管理功能机制，并发现与肠道溃疡的NSAID属性的相关性。口服给予常规NSAID（吲哚美辛、双氯芬酸、萘普生和氟比洛芬）、选择性环氧合酶（考克斯）-1抑制剂（SC-560）和选择性考克斯-2抑制剂（罗非考昔），24小时后检查肠粘膜。吲哚美辛可降低肠粘膜前列腺素E-2（PGE（2））的产生，引起肠蠕动亢进和细菌侵入，并上调iNOS表达和NO产生，导致出血性病变。其他NSAIDs同样抑制PGE（2）的产生，并引起出血性病变，伴有肠运动亢进和iNOS表达。PGE（2）和阿托品都能预防消炎痛引起的肠蠕动亢进，但氨苄青霉素不能，但所有这些药物不仅能抑制细菌入侵，还能抑制iNOS的表达，从而预防肠道病变。SC-560，而不是罗非昔布，引起PGE（2）产生减少，肠运动过度，细菌入侵和iNOS表达，但这种药物既不增加iNOS活性，也不引起肠损伤，因为PGE（2）产生的恢复是由于考克斯-2表达。食物剥夺完全衰减诱导型一氧化氮合酶的表达和损伤形成的吲哚美辛。总之，给予NSAID后小肠中iNOS的表达是由考克斯-1抑制引起的，并且在功能上与肠道运动过度和细菌侵袭相关。这一过程在对NSAID的肠溃疡反应中起主要致病作用。
We investigated the functional mechanisms underlying the expression of inducible nitric oxide (NO) synthase (iNOS) in the rat small intestine following the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and found a correlation with the intestinal ulcerogenic properties of NSAIDs. Conventional NSAIDs (indomethacin, dicrofenac, naproxen, and flurbiprophen), a selective cyclooxygenase (COX)-1 inhibitor (SC-560) and a selective COX-2 inhibitor (rofecoxib) were administered p.o., and the intestinal mucosa was examined 24 hours later. Indomethacin decreased prostaglandin E-2 (PGE(2)) production in the intestinal mucosa and caused intestinal hypermotility and bacterial invasion as well as the upregulation of iNOS expression and NO production, resulting in hemorrhagic lesions. Other NSAIDs similarly inhibited PGE(2) production and caused hemorrhagic lesions with intestinal hypermotility as well as iNOS expression. Hypermotility in response to indomethacin was prevented by both PGE(2) and atropine but not ampicillin, yet all these agents inhibited not only bacterial invasion but also expression of iNOS as well, resulting in prevention of intestinal lesions. SC-560, but not rofecoxib, caused a decrease in PGE(2) production, intestinal hypermotility, bacterial invasion, and iNOS expression, yet this agent neither increased iNOS activity nor provoked intestinal damage because of the recovery of PGE(2) production owing to COX-2 expression. Food deprivation totally attenuated both iNOS expression and lesion formation in response to indomethacin. In conclusion, the expression of iNOS in the small intestine following administration of NSAIDs results from COX-1 inhibition and is functionally associated with intestinal hypermotility and bacterial invasion. This process plays a major pathogenic role in the intestinal ulcerogenic response to NSAIDs.