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）。这些特征可能随着时间的推移而改变，以应对伴随OSA的各种扰动，最终导致这种疾病的恶化。我们的研究将探讨一种表型特征，即对二氧化碳和氧气的通气敏感性是否会在间歇性缺氧（OSA的标志）时增加，以及这种增加是否会导致OSA的恶化。此外，由于间歇性缺氧后的氧化应激在动物的呼吸驱动中具有增强作用，我们将研究这种机制是否有助于通气敏感性的增加并最终加剧OSA。我们还将确定抗氧化剂治疗是否会逆转这种效果。为了实现我们的目标，将解决以下具体目标：具体目标1旨在使用改良的再呼吸技术，在连续7天暴露于急性间歇性缺氧（AIH）之前和之后，测量清醒期间持续缺氧和高氧存在下对二氧化碳的通气反应。Specific Aim 2旨在测量AIH前后的夜间呼吸驱动和呼吸暂停严重程度，并确定AIH对这些指标的影响是否在CIH后加剧。通过检查缺氧时通气反应的变化和呼吸暂停期间食管压力的变化率，可以获得夜间呼吸驱动的测量。具体目标3和4将测量AIH前后的氧化应激，并将确定抗氧化治疗是否减轻AIH暴露后对二氧化碳的通气敏感性、夜间呼吸驱动和最终呼吸暂停严重程度的增加。提出的目标可能会对间歇性缺氧对通气敏感性和呼吸暂停严重程度的影响产生关键的见解。此外，我们的研究结果可能为使用抗氧化剂作为阻塞性睡眠呼吸暂停的潜在治疗方法提供了依据。当与其他潜在的创新疗法联合使用时，这种治疗方法对患有轻度或中度阻塞性睡眠呼吸暂停的个体特别有用。

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.