Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2
Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2
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DOI：
10.1172/jci6899
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发表时间：
2000-02-01
影响因子：
15.9
通讯作者：
Sartor, RB
中科院分区：
文献类型：
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作者：
Morteau, O;Morham, SG;Sartor, RB
为了研究 2 种环氧合酶 (COX) 同工型在肠道炎症中的作用，我们确定了缺乏 COX-1 或 COX-2 同工型的小鼠对自发性和诱导性急性结肠炎的易感性。我们用葡聚糖硫酸钠 (DSS) 治疗野生型、COX-1(-/-)、COX-2(-/-) 和杂合子小鼠以引发急性结肠炎症，并量化组织损伤、前列腺素 (PG) E-2 和白细胞介素 1 β。尽管在 COX-1-/- 小鼠中几乎检测不到基础肠道 PGE(2) 的产生，但在任一突变纯合子小鼠中均未检测到自发性胃肠道炎症。 COX-1(-/-) 和 COX-2(-/-) 小鼠均表现出对低剂量 DSS 的敏感性增加，而 DSS 会在野生型小鼠中引起轻度结肠上皮损伤。 COX-2(-/-)小鼠比COX-1(-/-)小鼠更容易受到影响，并且选择性药理学阻断COX-2会加剧COX-1(-/-)小鼠的损伤。在高剂量下，DSS 治疗对每个突变组中 50% 的动物致命，但所有野生型小鼠都存活下来。除COX-2(-/-)小鼠外，DSS处理增加了所有组中PGE(2)肠道分泌。这些结果表明，COX-1 和 COX-2 在肠粘膜的防御中起着至关重要的作用（诱导型 COX-2 在炎症过程中可能更活跃），并且在没有有害刺激的情况下，这两种异构体对于维持粘膜稳态都不是必需的。
To investigate roles in intestinal inflammation for the 2 cyclooxygenase (COX) isoforms, we determined susceptibility to spontaneous and induced acute colitis in mice lacking either the COX-1 or COX-2 isoform. We treated wild-type, COX-1(-/-), COX-2(-/-), and heterozygous mice with dextran sodium sulfate (DSS) to provoke acute colonic inflammation, and we quantified tissue damage, prostaglandin (PG) E-2, and interleukin-1 beta. No spontaneous gastrointestinal inflammation was detected in mice homozygous for either mutation, despite almost undetectable basal intestinal PGE(2) production in COX-1-/- mice. Both COX-1(-/-) and COX-2(-/-) mice showed increased susceptibility to a low-dose of DSS that caused mild colonic epithelial injury in wild-type mice. COX-2(-/-) mice were more susceptible than COX-1(-/-) mice, and selective pharmacologic blockade of COX-2 potentiated injury in COX-1(-/-) mice. At a high dose, DSS treatment was fatal to 50% of the animals in each mutant group, but all wild-type mice survived. DSS treatment increased PGE(2) intestinal secretion in all groups except COX-2(-/-) mice. These results demonstrate that COX-1 and COX-2 share a crucial role in the defense of the intestinal mucosa (with inducible COX-2 being perhaps more active during inflammation) and that neither isoform is essential in maintaining mucosal homeostasis in the absence of injurious stimuli.