Impact of intermittent hypoxia on ventilatory drive and apnea severity

描述(由申请人提供)：许多表型特征可能使人类易患阻塞性睡眠呼吸暂停(OSA)。这些特征可能会随着时间的推移而改变，以应对伴随着OSA的各种干扰，最终导致这种疾病的恶化。我们的建议将检查一个表型特征，即对二氧化碳和氧气的通气性敏感性，是否在间歇性低氧(阻塞性睡眠呼吸暂停的一个特征)时增加，以及这种增加是否导致阻塞性睡眠呼吸暂停综合征的加重。此外，由于间歇性低氧后的氧化应激在增强动物的呼吸动力方面具有作用，我们将研究这一机制是否有助于增加呼吸敏感性，并最终加剧阻塞性睡眠呼吸暂停。我们还将确定抗氧化剂的治疗是否能逆转这一效果。为了实现我们的目标，我们将实现以下具体目标：具体目标1旨在使用改进的重复呼吸技术，在连续7天的急性间歇低氧(AIH)暴露(慢性间歇低氧-CIH)之前和之后，测量清醒状态下持续低氧和高氧状态下对二氧化碳的换气反应。具体目的2旨在测量AIH前后夜间呼吸驱动和呼吸暂停的严重程度，并确定CIH后AIH对这些指标的影响是否加剧。夜间呼吸动力的测量将通过检查呼吸暂停期间呼吸反应的变化和食道压力的变化率来获得。特定的AIMS 3和4将测量AIH前后的氧化应激，并将确定抗氧化剂治疗是否减轻暴露于AIH后对二氧化碳的通风敏感性增加、夜间呼吸驱动以及最终的呼吸暂停严重程度。拟议的目标可能会对间歇性低氧对呼吸敏感性和呼吸暂停严重程度的影响提供关键的见解。此外，我们的发现可能为使用抗氧化剂作为阻塞性睡眠呼吸暂停综合征的潜在治疗方法提供依据。当与其他潜在的创新疗法结合使用时，这种治疗方法对患有轻度或中度阻塞性睡眠呼吸暂停综合征的个人可能特别有用。

DESCRIPTION (provided by applicant): A number of phenotypic traits may predispose humans to the development of obstructive sleep apnea (OSA). These traits may be altered over time in response to a variety of perturbations that accompany OSA, ultimately resulting in the exacerbation of this disorder. Our proposal will examine whether one phenotypic trait, the ventilatory sensitivity to carbon dioxide and oxygen, is increased in response to intermittent hypoxia (a hallmark of OSA), and whether this increase leads to exacerbation of OSA. Moreover, because oxidative stress following intermittent hypoxia has a role in enhancing respiratory drive in animals, we will examine whether this mechanism contributes to increases in ventilatory sensitivity and ultimately exacerbation of OSA. We will also determine whether treatment with antioxidants reverses this effect. To achieve our goals the following specific aims will be addressed: Specific Aim 1 is designed to measure the ventilatory response to carbon dioxide in the presence of sustained hypoxia and hyperoxia during wakefulness, using a modified rebreathing technique, before and after exposure to acute intermittent hypoxia (AIH) for 7 consecutive days (chronic intermittent hypoxia - CIH). Specific Aim 2 is designed to measure nocturnal respiratory drive and apnea severity before and after AIH, and to determine whether the impact of AIH on these measures is intensified after CIH. Measures of nocturnal respiratory drive will be obtained by examining changes in the ventilatory response to hypoxia and the rate of change of esophageal pressure during apnea. Specific Aims 3 & 4 will measure oxidative stress before and after AIH, and will determine whether antioxidant treatment mitigates increases in ventilatory sensitivity to carbon dioxide, nocturnal respiratory drive and ultimately apnea severity following exposure to AIH. The proposed aims are likely to yield critical insight into the impact that intermittent hypoxia has on ventilatory sensitivity and apnea severity. Moreover, our findings may provide the rationale for using antioxidants as a potential treatment for OSA. This treatment could be particularly useful in individuals who suffer from mild or moderate forms of OSA when used in conjunction with other potential innovative therapies.