Circadian Modulation of Breathing Stability and Respiratory Plasticity

描述(由申请人提供)： 摘要：睡眠中的呼吸不稳定是睡眠呼吸暂停的一个特征，其特征是呼吸暂停反复发作，然后是呼吸暂停过多。这些反复出现的循环导致间歇性低氧(IH)和睡眠过度唤醒，这可能导致许多病理生理状况，包括日间嗜睡和高血压。近年来，内源性昼夜节律在调节许多疾病的严重程度方面的作用已变得明显。因此，睡眠呼吸暂停的严重程度可能在一定程度上受到昼夜节律系统的调节，主要是通过改变影响呼吸稳定性的机制。这些改变可能包括化学反射特性的改变(即敏感性或反应阈值)或对上呼吸道肌肉活动的控制。因此，这项建议的首要目标是确定内源性昼夜节律是否直接或间接地通过呼吸可塑性的表达(分钟通气量和上呼吸道肌肉的长期促进)来调节机制，最终改善24小时昼夜周期中特定时间点的呼吸稳定性。我们的目标1 该提案将确定与夜间睡眠相比，白天的呼吸不稳定是否会减少。这一目标还将检验以下假设：与夜间相比，白天睡眠期间稳定性的提高与降低对二氧化碳的化学反射敏感性、增加二氧化碳储备和加强对上呼吸道肌肉的神经肌肉控制(即影响呼吸稳定性的机制)有关。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(即呼吸长期易化和上呼吸道肌肉活动的长期易化)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会导致呼吸稳定性的改善，超过间歇性低氧之前的措施。AIM 3旨在根据影响呼吸稳定性的机制的昼夜调节，确定睡眠呼吸暂停患者在下午或晚上消除呼吸事件所需的治疗压力是否会低于清晨。同样，这个目标将决定在暴露于IH或持续的轻度高碳酸血症后，呼吸可塑性启动后，在一天中的特定时间消除呼吸暂停所需的治疗压力是否较小。如果影响呼吸稳定性的呼吸可塑性的机制和形式受到昼夜节律的调节 这最终会影响睡眠呼吸暂停的治疗。患者可以在呼吸最稳定的时候安排午睡。同样，在呼吸稳定性增强的情况下，治疗呼吸暂停所需的治疗压力将会减少，这可能会改善治疗依从性。此外，新的辅助疗法，如间歇性低氧结合持续正压(即公认的睡眠呼吸暂停治疗方法)，可以降低治疗压力，特别是在呼吸可塑性和呼吸稳定性达到高峰时进行治疗。

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.