Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents
Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents
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DOI：
10.3109/00365521003797205
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发表时间：
2010-08-01
影响因子：
1.9
通讯作者：
Bjarnason, Ingvar T.
中科院分区：
文献类型：
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作者：
Hotz-Behofsits, Christoph;Simpson, Robert J.;Bjarnason, Ingvar T.
Objective.人们普遍认为，环氧合酶1（考克斯-1）的抑制，以及随之而来的粘膜中的前列腺素的减少沿着伴随着考克斯-2的抑制，是非甾体抗炎药（NSAID）诱导的肠病的关键。我们研究了考克斯-1、考克斯-2的作用以及药物的局部作用在NSAID肠病中的作用。材料和方法。我们对野生型、考克斯-1和考克斯-2缺陷小鼠给予R-2-苯基丙酸（与常规NSAID具有相同的局部特征，但不影响考克斯酶）、常规NSAID氟比洛芬和选择性考克斯-2抑制剂塞来昔布后的小肠损伤和前列腺素E（2）水平进行了定量。我们还测量了给予选择性考克斯-1抑制剂SC-560和NSAID的大鼠的肠道通透性和炎症。在基线和给药后评估参数。结果R-2-苯基丙酸在给予塞来昔布的考克斯-2（-/-）和野生型小鼠中引起小肠损伤，但在野生型或考克斯-1（-/-）小鼠中没有。给予R-2-苯基丙酸的小鼠体内PGE（2）水平升高。吲哚美辛增加了大鼠的渗透性并引起炎症。结论.考克斯-2缺失（或抑制）和NSAID的局部作用的组合导致NSAID肠病的特征性变化，而没有伴随的考克斯-1抑制和/或相关的粘膜异黄酮减少。考克斯-2似乎比考克斯-1对维持小肠完整性更重要。
Objective. It is widely thought that cyclooxygenase 1 (COX-1) inhibition with consequential decreases in mucosal prostaglandins, along with concomitant inhibition of COX-2, is pivotal in nonsteroidal anti-inflammatory drug-induced (NSAID) enteropathy. We examined the role of COX-1, COX-2 and topical effects of drugs in NSAID enteropathy. Material and methods. We quantified small intestinal damage and prostaglandin E(2) levels in wild-type, COX-1 and COX-2 deficient mice after administration of R-2-phenylpropionic acid (which has the same topical characteristics as conventional NSAIDs but does not affect the COX enzymes), the conventional NSAIDs flurbiprofen and the selective COX-2 inhibitor celecoxib. We also measured intestinal permeability and inflammation in rats given the selective COX-1 inhibitor SC-560 and NSAIDs. The parameters were assessed at baseline and after administration of the drugs. Results. R-2-phenylpropionic acid caused small intestinal damage in COX-2(-/-) and wild-type mice given celecoxib, but not in wild type or COX-1(-/-) mice. PGE(2) levels in mice dosed with R-2-phenylpropionic acid were elevated. Indomethacin raised permeability and caused inflammation in rats. Conclusions. The combination of COX-2 absence (or inhibition) and the topical effect of NSAIDs lead to changes characteristic of NSAID enteropathy without concomitant COX-1 inhibition and/or associated decreases in mucosal prostaglandins. COX-2 appears to be more important for maintaining small bowel integrity than COX-1.