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Role of cyclooxygenase-2 in gastric mucosal defense.

机译：环氧合酶2在胃黏膜防御中的作用。

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摘要

Two isoenzymes of cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, COX-1 and COX-2, have been identified. COX-1 was proposed to regulate physiological functions, COX-2 to mediate pathophysiological reactions such as inflammation. In particular, it was suggested that maintenance of gastric mucosal integrity relies exclusively on COX-1. Recently, it was shown that a selective COX-1 inhibitor does not damage the mucosa in the healthy rat stomach, although mucosal prostaglandin formation is near-maximally suppressed. However, concurrent treatment with a COX-1 and a COX-2 inhibitor induces severe gastric damage. This indicates that in normal mucosa both COX-1 and COX-2 have to be inhibited to evoke ulcerogenic effects. In the acid-challenged rat stomach inhibition of COX-1 alone is associated with dose-dependent injury which is aggravated by additional inhibition of COX-2 activity or prevention of acid-induced up-regulation of COX-2 expression by dexamethasone. After acid exposure, COX-2 inhibitors cause substantial gastric injury when nitric oxide formation is suppressed or afferent nerves are defunctionalized. Ischemia-reperfusion of the gastric artery increases levels of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone aggravate ischemia-reperfusion-induced mucosal damage up to 4-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE2. Furthermore, the protective effects elicited by a mild irritant or intragastric peptone perfusion are antagonized by COX-2 inhibitors. Finally, COX-2 expression is increased in experimental ulcers. COX-2 inhibitors delay the healing of chronic gastric ulcers in experimental animals and decrease epithelial cell proliferation, angiogenesis and maturation of the granulation tissue to the same extent as non-steroidal anti-inflammatory drugs. These observations indicate that, in contrast to the initial concept, COX-2 plays an important role in gastric mucosal defense.
机译：已经确定了环加氧酶（COX）的两种同工酶，这是前列腺素（PG）生物合成中的关键酶COX-1和COX-2。有人建议使用COX-1调节生理功能，建议使用COX-2调节炎症等病理生理反应。特别是，有人提出维持胃粘膜完整性仅依赖于COX-1。近来，已显示出选择性COX-1抑制剂不会损害健康大鼠胃中的粘膜，尽管粘膜前列腺素的形成几乎被最大程度地抑制了。但是，同时使用COX-1和COX-2抑制剂治疗会引起严重的胃部损伤。这表明在正常的粘膜中，必须同时抑制COX-1和COX-2才能引起溃疡。在酸激发的大鼠中，单独抑制COX-1与剂量依赖性损伤有关，这种损伤会因另外抑制COX-2活性或阻止地塞米松对酸诱导的COX-2表达上调而加剧。暴露于酸中后，当一氧化氮的形成受到抑制或传入神经失去功能时，COX-2抑制剂会导致严重的胃损伤。胃动脉缺血再灌注增加了COX-2的水平，但没有增加COX-1 mRNA的水平。 COX-2抑制剂或地塞米松可加重缺血再灌注引起的粘膜损伤，最高可达4倍，而同时给予16,16-二甲基-PGE2则可消除这种作用。此外，COX-2抑制剂可拮抗轻度刺激性或胃内蛋白per灌注引起的保护作用。最后，在实验性溃疡中COX-2表达增加。 COX-2抑制剂可延缓实验动物中慢性胃溃疡的愈合，并与非甾体类抗炎药一样，减少上皮细胞的增殖，肉芽组织的血管生成和成熟。这些观察结果表明，与最初的概念相反，COX-2在胃粘膜防御中起重要作用。

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