Effects of acute and chronic hypoxia on rat lung cyclooxygenase.
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.
Chida
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Pulmonary Hypertension Center, University of Colorado Health Science Center, Denver 80262, USA.
Voelkel
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000208:Acute Disease; D000818:Animals; D015152:Blotting, Northern; D002908:Chronic Disease; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004790:Enzyme Induction; D000860:Hypoxia / Q000201:enzymology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D012333:RNA, Messenger; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019331:NG-Nitroarginine Methyl Ester