Circadian Modulation of Breathing Stability and Respiratory Plasticity

描述（由申请人提供）： 摘要：睡眠期间的呼吸不稳定是睡眠呼吸暂停的标志，其特征在于呼吸暂停随后呼吸过度的反复循环。这些循环导致间歇性缺氧（IH）和睡眠过度觉醒，这可能导致许多病理生理状况，包括白天嗜睡和高血压。近年来，内源性昼夜节律在调节许多疾病的严重程度中的作用已经变得明显。因此，睡眠呼吸暂停的严重程度可以部分地由昼夜节律计时系统调节，主要通过影响呼吸稳定性的机制的修改。这些改变可能包括化学反射特性（即敏感性或反应阈值）的改变或上气道肌肉活动的控制。因此，该提议的主要目的是确定内源性昼夜节律是否通过呼吸可塑性的表达（分钟通气量和上气道肌肉的长期促进）直接或间接地调节机制，其最终改善24小时昼夜周期内特定点的睡眠期间的呼吸稳定性。 我们的目标1 建议将确定与夜间睡眠相比，白天呼吸不稳定性是否减少。这一目标还将检验以下假设：与夜间相比，白天睡眠期间增加的稳定性与对二氧化碳的化学反射敏感性降低、二氧化碳储备增加和上气道肌肉的神经肌肉控制增强（即影响呼吸稳定性的机制）相关。我们建议的目标2将确定促进呼吸稳定性的呼吸可塑性形式（即上呼吸道肌肉活动的长期促进和长期促进）是否在白天比夜间增强。同样，这一目标将确定这些形式的可塑性的增强是否导致呼吸稳定性的改善，其超过暴露于间歇性缺氧之前获得的测量。目的3旨在根据影响呼吸稳定性的机制的昼夜节律调节，确定消除睡眠呼吸暂停患者呼吸事件所需的治疗压力在下午或晚上是否低于清晨。同样，这一目标将确定在暴露于IH或持续轻度高碳酸血症后，呼吸可塑性开始后，在一天中给定时间消除呼吸暂停所需的治疗压力是否更小。 如果影响呼吸稳定性的呼吸可塑性机制和形式受到昼夜节律的调节， 睡眠呼吸暂停的治疗方法有哪些？患者可以从安排在呼吸最稳定的时候小睡中获益。同样，在呼吸稳定性增加的情况下，治疗呼吸暂停所需的治疗压力将更小，这可以改善治疗依从性。此外，新的辅助疗法，如间歇性低氧与持续气道正压通气联合给药（即，睡眠呼吸暂停的成熟治疗），可能会导致治疗压力降低，特别是如果在呼吸可塑性和呼吸稳定性处于峰值时给予治疗。

DESCRIPTION (provided by applicant): ABSTRACT: Breathing instability during sleep, which is a hallmark of sleep apnea, is characterized by recurring cycles of apnea followed by hyperpnea. These recurring cycles lead to intermittent hypoxia (IH) and excessive arousal from sleep, which may result in a number of pathophysiological conditions including daytime sleepiness and hypertension. In recent years, the role of an endogenous circadian rhythm in modulating the severity of many disorders has become evident. Accordingly, the severity of sleep apnea may be modulated in part by a circadian timing system, principally through the modification of mechanisms that impact on breathing stability. These modifications might include alterations in chemoreflex properties (i.e. sensitivity or threshold of response) or control of upper airway muscle activity. Thus, the overlying objective of this proposal is to determine if an endogenous circadian rhythm modulates mechanisms, directly or indirectly via the expression of respiratory plasticity (long-term facilitation of minute ventilation and upper airway muscle), which ultimately improves breathing stability during sleep at specific points within a 24 hour day/night cycle. Aim 1 of our proposal will establish if breathing instability is reduced during daytime compared to nighttime sleep. This aim will also test the hypothesis that increased stability is associated with reduced chemoreflex sensitivity to carbon dioxide, an increased carbon dioxide reserve and enhanced neuromuscular control of upper airway muscles (i.e. mechanisms that impact on breathing stability) during sleep in the daytime compared to the nighttime. Aim 2 of our proposal will establish if forms of respiratory plasticity that promote breathing stability (i.e. ventilatory lon-term facilitation and long-term facilitation of upper airway muscle activity) are enhanced in the day compared to the night. Likewise, this aim will establish if enhancement of these forms of plasticity leads to an improvement in breathing stability that exceeds measures obtained before exposure to intermittent hypoxia. Aim 3 is designed to determine whether or not the therapeutic pressure required for the elimination of breathing events in individuals with sleep apnea will be less in the afternoon or evening compared to the early morning in accordance with circadian modulation of mechanisms that impact breathing stability. Likewise, this aim will determine if the therapeutic pressure required to eliminate apnea at a given time of day is less after the initiatio of respiratory plasticity following exposure to IH or sustained mild hypercapnia. If mechanisms and forms of respiratory plasticity that impact on breathing stability are modulated by a circadian rhythm this will ultimately impact on the treatment of sleep apnea. Patients could derive benefit from scheduling naps at times when breathing is most stable. Likewise, therapeutic pressures required to treat apnea would be less under conditions of increased breathing stability which could improve treatment compliance. Moreover, novel adjunct therapies such as intermittent hypoxia administered in combination with continuous positive airway pressure (i.e. a well-established treatment for sleep apnea) could result in reduced therapeutic pressures particularly if treatment was administered at times when the magnitude of respiratory plasticity and breathing stability were at their peak.