Intermittent Hypoxia and Cardiopulmonary Adaptation

间歇性缺氧与心肺适应

• 批准号: RGPIN-2014-05643
• 负责人: Foster, Glen
• 金额: $ 2.26万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683934
• 关键词: Intermittent; Hypoxia; Cardiopulmonary; Adaptation

The cardiovascular, respiratory and autonomic nervous systems interact to maintain a relative homeostasis during physiological stressors (e.g., exercise, heat, hypoxia). The human body's ability to adapt when exposed to low levels of oxygen (called hypoxia) highlights an important multi-system coordination of physiological responses. The integrated study of these systems provides insight into their adaptation to hypoxia and contributes to our comprehensive understanding of basic human physiology. The long-term objective of my research program is to understand how the respiratory, cardiovascular, and autonomic nervous systems interact, respond, and adapt to hypoxia. **Important differences in the cardiopulmonary systems response to hypoxia of varying intensity, duration, and repetition [i.e. intermittent hypoxia (IH)] have been identified yet our understanding of the mechanisms controlling these differences is poorly understood. Cardiopulmonary adaptation to IH is of particular interest in light of the growing use of IH training with athletes (e.g., hockey, Olympics, mountain climbers). As Canada continues to remain strong at competitive sports, it is prudent to fully explore the basic physiological mechanisms behind the adaptations that take place when healthy humans are exposed to hypoxia. **The research program is divided into two research themes with specific research objectives. In theme I, a series of studies will be aimed at understanding the relationship between sympathetic nerve activity, vascular diameter, and blood flow during and following exposure to hypoxia. Exposure to IH in animals and humans leads to increases in chemoreceptor sensitivity, sympathetic activity, arterial blood pressure, and oxidative stress. The specific mechanisms responsible for these adaptations to IH are unknown; however, our preliminary investigations suggest signaling through the renin-angiotensin system might be involved. Two research objectives have been identified: (1) to determine the differential effect of sustained versus IH on neurovascular coupling in the peripheral and cerebral circulations; and (2) to determine the involvement of the renin-angiotensin system in potentiating sympathoexcitation following IH. In theme II, a series of studies will be aimed at identifying how hypoxia leads to the opening of intrapulmonary arteriovenous anastomoses (IPAVA). IPAVA are pulmonary vessels that bypass the gas exchange surface of the lung and thereby decrease oxygen delivery. This research theme will identify a potential role for IPAVA in protecting pulmonary capillaries from high perfusion pressures that occur during hypoxia. In addition, it will develop a new image analysis tool for quantifying blood flow through IPAVA and determine the humoral and mechanical stimuli responsible for opening and closing IPAVA during hypoxia. For theme II, two research objectives have been identified: (1) to develop and validate a quantitative analysis tool for measuring blood flow through IPAVA from agitated saline contrast echocardiograms; and (2) to determine the relative importance of arterial hypoxia versus increased pulmonary artery pressure in mediating the opening of IPAVA during acute hypoxia. **The proposed research program is a logical extension and incorporates new technologies and discoveries made during my NSERC postdoctoral fellowship. All HQP will receive leadership and project management training, develop independent intellectual research capacity, collaborate with associated laboratories, and will drive the development of new methodologies and innovation. Also, HQP will be involved in writing and publishing their results in high impact physiology journals and conference presentations.

心血管、呼吸和自主神经系统相互作用以在生理应激（例如，运动、热、缺氧）。 人体在暴露于低水平氧气（称为缺氧）时的适应能力突出了生理反应的重要多系统协调。 这些系统的综合研究提供了深入了解他们的适应缺氧，并有助于我们全面了解基本的人体生理学。 我的研究计划的长期目标是了解呼吸，心血管和自主神经系统如何相互作用，反应和适应缺氧。 ** 心肺系统对不同强度、持续时间和重复性缺氧[即间歇性缺氧（IH）]的反应存在重要差异，但我们对控制这些差异的机制的理解仍知之甚少。 鉴于越来越多的运动员使用IH训练（例如，曲棍球、奥运会、登山运动员）。 随着加拿大继续在竞技体育方面保持强势，充分探索健康人暴露于缺氧时发生的适应背后的基本生理机制是明智的。 ** 研究计划分为两个研究主题，具有特定的研究目标。 在主题I中，一系列的研究将旨在了解交感神经活动，血管直径和血流之间的关系，以及暴露于缺氧。 在动物和人类中暴露于IH导致化学感受器敏感性、交感神经活性、动脉血压和氧化应激的增加。 负责这些适应IH的具体机制是未知的，但是，我们的初步研究表明，通过肾素-血管紧张素系统的信号可能参与。 已经确定了两个研究目标：（1）确定持续与IH对外周和脑循环中神经血管偶联的不同影响;（2）确定肾素-血管紧张素系统参与IH后增强交感兴奋。 在主题II中，一系列研究旨在确定缺氧如何导致肺内动静脉栓塞（IPAVA）的开放。 IPAVA是绕过肺的气体交换表面从而减少氧气输送的肺血管。 本研究主题将确定IPAVA在保护肺毛细血管免受缺氧期间发生的高灌注压的潜在作用。 此外，它将开发一种新的图像分析工具，用于量化通过IPAVA的血流，并确定在缺氧期间负责打开和关闭IPAVA的体液和机械刺激。 对于主题II，已经确定了两个研究目标：（1）开发和验证定量分析工具，用于从搅拌盐水造影超声心动图测量通过IPAVA的血流;（2）确定急性缺氧期间动脉缺氧与肺动脉压升高在介导IPAVA开放中的相对重要性。 ** 拟议的研究计划是一个合乎逻辑的延伸，并结合了新技术和发现在我的NSERC博士后奖学金。 所有HQP将接受领导力和项目管理培训，发展独立的智力研究能力，与相关实验室合作，并将推动新方法和创新的发展。 此外，HQP将参与撰写并在高影响力的生理学期刊和会议报告中发表他们的结果。