The Role of Cytokines in Sleepiness and Sleep Apnea

描述（由申请人提供）：白天过度嗜睡（EDS）是一个主要的公共卫生问题，部分原因是患有EDS的人通常在工作中效率低下，更容易发生事故，并且通常在白天无法正常工作。EDS是阻塞性睡眠呼吸暂停（OSA）患者的主要表现之一，常见于无睡眠呼吸暂停的肥胖患者。EDS的机制尚不清楚。我们已经证明，促炎和诱导疲劳的细胞因子、肿瘤坏死因子-a （TNFa）和白细胞介素-6 （IL-6）在病理性嗜睡（如睡眠呼吸暂停）或实验诱导嗜睡（如完全剥夺睡眠）的情况下升高。由初始拨款（HL-64415）资助的进一步工作表明(1)即使轻度睡眠限制为每晚6小时，持续1周也与嗜睡增加、表现下降、TNFa和IL-6水平升高有关；(2)肥胖OSA患者的高细胞因子血症及其相关的胰岛素抵抗并不能通过最常见的治疗方法逆转，即持续气道正压通气（CPAP）。此外，中和肥胖窒息患者的TNFa可显著降低EDS。在这个应用中，我们建议研究恢复性睡眠、肥胖和中年对正常睡眠者睡眠限制一周后的嗜睡、表现和炎症细胞因子的影响（具体目标1-3）。我们假设两晚的恢复性睡眠并不能充分逆转轻度睡眠限制的不良影响，而肥胖和中年则会加剧轻度睡眠限制的不良影响。此外，我们建议测试(a)非肥胖型呼吸暂停患者以及体重、年龄和性别匹配的对照组中细胞因子和脂肪因子（瘦素和脂联素）和胰岛素抵抗/内脏脂肪的24小时昼夜节律模式；(b)在交叉安慰剂对照设计中使用CPAP的效果（特定目的4）。我们假设，与对照组相比，有症状的非肥胖性呼吸暂停患者表现出更高水平的IL-6、TNFa和胰岛素抵抗/内脏脂肪，并且与假CPAP相比，CPAP对免疫/代谢异常有轻微但显著的影响。在这些研究中，我们将使用一系列实验技术，包括夜间多导睡眠图、MSLT、PVT、活动图、24小时血液采样、皮质醇、TNFa、IL-6、瘦素、脂联素和腹部计算机断层扫描（CT）检测体脂分布、CPAP和假CPAP。这些研究将为TNFa和IL-6在EDS和OSA中的作用提供额外的证据，并为开发新的治疗干预措施奠定基础。

DESCRIPTION (provided by applicant): Excessive daytime sleepiness (EDS) is a major public health concern in part because individuals suffering from EDS often are not productive at work, are more susceptible to accidents and generally are unable to function normally during the day. EDS is 1 of the major manifestations of individuals suffering from obstructive sleep apnea (OSA) and is frequently reported by obese individuals without sleep apnea. The mechanisms underlying EDS are not clear. We have demonstrated that the pro-inflammatory and fatigue-inducing cytokines, tumor necrosis factor-a (TNFa) and interleukin-6 (IL-6) are elevated in conditions of pathological sleepiness, e.g., sleep apnea, or in experimentally-induced sleepiness, e.g., following total sleep deprivation. Further work funded by the initial grant (HL-64415) demonstrated that (1) even mild sleep restriction to 6 hours per night for 1 week is associated with increased sleepiness, decreased performance, and increased levels of TNFa and IL-6, and (2) hypercytokinemia and its associated insulin resistance in obese OSA patients is not reversed by the most common treatment for this disorder, i.e., continuous positive airway pressure (CPAP). Additionally, neutralizing TNFa in obese apneics reduces EDS markedly and significantly. In this application, we propose to study the effects of recovery sleep, obesity, and middle-age on sleepiness, performance, and inflammatory cytokines after one week of sleep restriction in normal sleepers (specific aims 1-3). We hypothesize that recovery sleep for 2 nights does not adequately reverse the adverse effects of mild sleep restriction, whereas obesity and middle-age augment the adverse effects of mild sleep restriction. Furthermore, we propose to test (a) 24-hour circadian pattern of cytokines and adipokines (leptin and adiponectin), and insulin resistance/visceral fat in nonobese apneics, and in weight, age, and gender matched controls; and (b) the effects of CPAP use in a cross-over placebo controlled design (specific aim 4). We hypothesize that symptomatic nonobese apneics exhibit higher levels of IL-6, TNFa, and insulin resistance/visceral fat compared to controls and that CPAP compared to sham CPAP has a mild but significant effect on the immune/metabolic aberrations. In these studies, we will use a series of experimental techniques including nighttime polysomnography, MSLT, PVT, actigraphy, 24-hour blood sampling, and assays for cortisol, TNFa, IL-6, leptin, adiponectin, and abdominal computerized tomography (CT) for body fat distribution, CPAP, and Sham CPAP. These studies collectively will provide additional evidence for a role of TNFa and IL-6 in EDS and OSA and lay the foundation for the development of novel therapeutic interventions.