The Role of Cytokines in Sleepiness and Sleep Apnea

细胞因子在嗜睡和睡眠呼吸暂停中的作用

• 批准号: 6980342
• 负责人: ALEXANDROS N VGONTZAS
• 金额: $ 25.64万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6980342
• 关键词: actigraphy; blood chemistry; body composition; circadian rhythms; clinical research; human subject; human therapy evaluation; insulin sensitivity /resistance; interleukin 6; leptin; obesity; patient oriented research; polysomnography; positive pressure breathing; respiratory therapy; sleep; sleep apnea; sleep deprivation; tumor necrosis factor alpha; wakefulness

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.

描述（由申请人提供）：过度的白天嗜睡（EDS）是一个主要的公共卫生问题，部分原因是患有ED的人通常在工作中没有效率，更容易发生事故，并且通常在白天无法正常运作。 EDS是患有阻塞性睡眠呼吸暂停（OSA）的个体的主要表现，并且经常由没有睡眠呼吸暂停的肥胖个体报告。 ED的基础机制尚不清楚。我们已经证明，在病理困倦的条件下，例如睡眠呼吸暂停或实验性诱导的嗜睡（例如，在总的睡眠衰竭之后），促炎和诱导的细胞因子，肿瘤坏死因子-A（TNFA）和白介素6（IL-6）升高。最初赠款（HL-64415）资助的进一步的工作表明，（1）即使轻度睡眠限制至每晚6小时，1周也与嗜睡，性能降低，TNFA和IL-6的水平升高以及（2）高胞度血症及其在肥胖OSA患者中相关的胰岛素耐药性的压力均无法通过这种持续的阳性（即持续）。另外，肥胖猿中中和TNFA显着降低了EDS。在此应用中，我们建议研究恢复睡眠，肥胖和中年对嗜睡，性能和炎症细胞因子的影响，在正常卧铺的睡眠限制一周后（特定的目标1-3）。我们假设恢复睡眠2晚并不能充分扭转轻度睡眠限制的不利影响，而肥胖和中年龄增强了轻度睡眠限制的不利影响。此外，我们建议测试（a）24小时的细胞因子和脂肪因子（瘦素和脂联素）的昼夜节律模式，以及非肥胖症中的胰岛素抵抗/内脏脂肪，体重，年龄和性别匹配的控制； （b）CPAP在交叉安慰剂控制设计中使用的影响（特定目标4）。我们假设有症状的非肥胖呼吸暂停表现出更高水平的IL-6，TNFA和胰岛素抵抗/内脏脂肪与对照组相比，与Sham CPAP相比，CPAP对免疫/代谢畸变具有轻微但显着影响。在这些研究中，我们将使用一系列实验技术，包括夜间多症，MSLT，Pvt，Actigraphy，24小时的血液采样以及用于皮质醇，TNFA，IL-6，Leptin，脂结蛋白，脂结蛋白和腹部计算机术（CT）的皮质醇，TNFA，IL-6，用于体内脂肪脂肪脂肪的分布，CPAP和SHAM CPAP。这些研究集体将为EDS和OSA中TNFA和IL-6的作用提供其他证据，并为开发新的治疗干预措施奠定了基础。