Neural Plasticity During Acclimatization to Hypoxia

 描述（由申请人提供）：本提案的总体目标是确定中枢神经系统可塑性的分子信号，这些信号在慢性缺氧期间改变呼吸的反射控制。这项研究意义重大，因为它解决了肺医学中一个基本但未回答的问题：肺部疾病引起的慢性低氧血症是否会发生呼吸控制的变化，如果是这样，是否存在个体差异以及它们如何影响疾病的进展？我们已经开发出在有意识行为的实验室啮齿动物模型中在分子水平上研究基本问题的方法，这些实验的结果产生了我们能够在人类中进行测试的假设。具体来说，我们已经表明，常见的抗炎药布洛芬块在啮齿动物和健康人慢性缺氧期间通气和呼吸敏感性的时间依赖性增加。这提出了令人兴奋的新问题，即炎症信号在呼吸的化学反射控制中对健康和正常可塑性的作用。例如，炎症对于缺氧的适应性训练是必要的，当O2可用性长时间降低时，通过增加O2供应是有益的，但是细菌感染的炎症可以减少通气和O2供应，这会加剧病情。此外，我们有初步的数据表明，转录因子缺氧诱导因子-1 α（HIF-1α）是必要的，在脑干呼吸中心的正常发育， 在转基因小鼠中对低氧的习服。在这里，我们建议测试的假设，炎症信号和HIF-1α是必要的可塑性在控制呼吸慢性持续缺氧。在三个具体目标中，我们将检验慢性缺氧化学反射可塑性需要（1）脑干呼吸中枢NF-κB和HIF-1α的激活，（2）小胶质细胞的颈动脉体化学感受器传入激活，随后是维持炎症和HIF-1α反应的星形胶质细胞激活，（3）尽管HIF-2α可影响呼吸的稳定性，但由于活性氧（ROS）在慢性缺氧时并不发生变化，因此HIF-2α在脑干中的其他亚型是不必要的。对于缺氧和炎症同时发生的常见临床情况，例如COPD急性加重或ICU脓毒症后脱离机械通气，提出这些问题可能很重要。

 DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the molecular signals for plasticity in central nervous system that change the reflex control of breathing during chronic hypoxia. This research is significant because it addresses a fundamental but unanswered question in pulmonary medicine: Do changes in the control of breathing occur with chronic hypoxemia from lung disease and, if so, are there individual differences and how do they affect the progression of disease? We have developed methods to study the basic problem at the molecular level in conscious behaving laboratory rodent models, and results from these experiments have produced hypotheses that we have been able to test in humans. Specifically, we have shown that the common anti-inflammatory drug ibuprofen blocks time dependent increases in ventilation and ventilatory sensitivity to oxygen during chronic hypoxia in rodents and in healthy humans. This poses exciting new questions about the role of inflammatory signals for healthy and normal plasticity in the chemoreflex control of breathing. For example, inflammation is necessary for ventilatory acclimatization to hypoxia, which is beneficial by increasing O2 supply when O2 availability is decreased for long periods of time, but inflammation with bacterial infection can decrease ventilation and O2 supply, which exacerbates conditions. Also, we have preliminary data showing the transcription factor hypoxia inducible factor-1α (HIF-1α) is necessary in brainstem respiratory centers for normal ventilatory acclimatization to hypoxia in transgenic mice. Here we propose to test the hypothesis that both inflammatory signals and HIF-1α are necessary for plasticity in the control of breathing with chronic sustained hypoxia. In three specific aims, we will test the hypotheses that chemoreflex plasticity with chronic hypoxia requires (1) activation of NF-κB and HIF-1α in brainstem respiratory centers, (2) carotid body chemoreceptor afferent activation of microglia followed by astroglia activation that sustains an inflammatory and HIF-1α response, and (3) other isoforms of HIF in the brainstem are not necessary because reactive oxygen species (ROS) are not changing there with chronic hypoxia, although HIF-2α can affect the stability of breathing. Answering such questions could be important for common clinical scenarios where hypoxia and inflammation occur together, for example in COPD exacerbations or weaning from mechanical ventilation after sepsis in the ICU.