Department Farmaco-Biologico, School of Pharmacy, University of Messina, Messina, Italy.
J Appl Physiol (1985). 2012 Dec 1;113(11):1684-9. doi: 10.1152/japplphysiol.00922.2012. Epub 2012 Oct 4.
It has been proposed that relative changes of oxygen availability, rather than steady-state hypoxic or hyperoxic conditions, play an important role in hypoxia-inducible factor (HIF) transcriptional effects. According to this hypothesis describing the "normobaric oxygen paradox", normoxia following a hyperoxic event is sensed by tissues as an oxygen shortage, upregulating HIF-1 activity. With the aim of confirming, at cellular and at functional level, that normoxia following a hyperoxic event is "interpreted" as a hypoxic event, we report a combination of experiments addressing the effects of an intermittent increase of oxygen concentration on HIF-1 levels and the activity level of specific oxygen-modulated proteins in cultured human umbilical vein endothelial cells and the effects of hemoglobin levels after intermittent breathing of normobaric high (100%) and low (15%) oxygen in vivo in humans. Our experiments confirm that, during recovery after hyperoxia, an increase of HIF expression occurs in human umbilical vein endothelial cells, associated with an increase of matrix metalloproteinases activity. These data suggest that endothelial cells "interpret" the return to normoxia after hyperoxia as a hypoxic stimulus. At functional level, our data show that breathing both 15 and 100% oxygen 30 min every other day for a period of 10 days induces an increase of hemoglobin levels in humans. This effect was enhanced after the cessation of the oxygen breathing. These results indicate that a sudden decrease in tissue oxygen tension after hyperoxia may act as a trigger for erythropoietin synthesis, thus corroborating the hypothesis that "relative" hypoxia is a potent stimulator of HIF-mediated gene expressions.
有人提出，氧供应的相对变化，而不是稳定的低氧或高氧条件，在缺氧诱导因子 (HIF) 的转录效应中发挥重要作用。根据描述“常压氧悖论”的这一假说，在经历高氧事件后，组织会将常氧感知为缺氧，从而上调 HIF-1 活性。为了在细胞和功能水平上证实高氧事件后的常氧“被解释”为低氧事件，我们报告了一系列实验结果，这些实验旨在探讨氧浓度间歇性增加对 HIF-1 水平和特定氧调节蛋白活性的影响，以及在人体中间歇性呼吸常压高（100%）和低（15%）氧对血红蛋白水平的影响。我们的实验证实，在高氧恢复期间，人脐静脉内皮细胞中 HIF 表达增加，同时基质金属蛋白酶活性增加。这些数据表明，内皮细胞将高氧后恢复常氧“解释”为低氧刺激。在功能水平上，我们的数据表明，在 10 天的时间里，每隔一天呼吸 15%和 100%的氧气 30 分钟，会导致人体血红蛋白水平升高。停止吸氧后，这种效应增强。这些结果表明，高氧后组织氧张力的突然下降可能作为促红细胞生成素合成的触发因素，从而证实了“相对”缺氧是 HIF 介导的基因表达的有力刺激物的假说。
