Chida M, Voelkel N F
Pulmonary Hypertension Center, University of Colorado Health Science Center, Denver 80262, USA.
Am J Physiol. 1996 May;270(5 Pt 1):L872-8. doi: 10.1152/ajplung.1996.270.5.L872.
Cyclooxygenase-2 (COX-2) is an inducible cyclooxygenase enzyme and may play an important role in the pathogenesis of lung injury and in pulmonary vascular remodeling. In this study we determined the effects of acute or chronic hypoxia on COX-2 induction and its modulation by .NO and adenosine 3'-5'-cyclic monophosphate (cAMP). Isolated perfused rat lungs were exposed to a normoxic gas mixture or a hypoxic gas mixture for 3 h. Northern blot analysis showed that 3 h of acute hypoxia were sufficient to increase COX-2 but not COX-1 transcripts in the lung. COX-2 expression induced by acute hypoxia was enhanced by an inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester, and was suppressed by sodium nitroprusside, meclofenamate, and H-7 (an inhibitor of protein kinase A and C). COX-2 expression was also enhanced by dibutyryl cAMP and iloprost, a prostacyclin analogue. In contrast, 2 wk of chronic hypobaric hypoxia did not enhance COX-2 expression in the lung, but increased COX-2 protein levels, as assessed by Western blots. We conclude that acute hypoxia induces COX-2 gene expression in rat lung and that COX-2 induction by acute hypoxia is modulated by .NO, cAMP, and cyclooxygenase products. In particular, prostacyclin produced by the lung during hypoxia or shear stress induces lung COX-2 expression via a positive feedback mechanism.
环氧化酶-2（COX-2）是一种可诱导的环氧化酶，可能在肺损伤发病机制及肺血管重塑中发挥重要作用。在本研究中，我们确定了急性或慢性缺氧对COX-2诱导作用的影响，以及一氧化氮（.NO）和3'-5'-环磷酸腺苷（cAMP）对其的调节作用。将离体灌注的大鼠肺暴露于常氧气体混合物或低氧气体混合物中3小时。Northern印迹分析表明，3小时的急性缺氧足以增加肺中COX-2而非COX-1的转录本。急性缺氧诱导的COX-2表达被一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯增强，而被硝普钠、甲氯芬那酸和H-7（蛋白激酶A和C的抑制剂）抑制。COX-2表达也被二丁酰cAMP和前列环素类似物伊洛前列素增强。相反，2周的慢性低压缺氧并未增强肺中COX-2的表达，但通过蛋白质印迹法评估发现其增加了COX-2蛋白水平。我们得出结论，急性缺氧诱导大鼠肺中COX-2基因表达，且急性缺氧诱导的COX-2受.NO、cAMP和环氧化酶产物调节。特别是，肺在缺氧或剪切应力期间产生的前列环素通过正反馈机制诱导肺COX-2表达。
