The Role of Cytokines in Sleepiness and Sleep Apnea

描述(申请人提供)：日间过度嗜睡(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，通常无法在白天正常运作。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背后的机制尚不清楚。我们已经证明，致炎和疲劳诱导的细胞因子、肿瘤坏死因子-α(TNFa)和白介素6(IL-6)在病理性嗜睡条件下(如睡眠呼吸暂停)或在实验诱导的嗜睡条件下(如完全睡眠剥夺后)会升高。由最初的赠款(HL-64415)资助的进一步工作表明：(1)即使是轻微的睡眠限制，每晚6小时，持续一周，也与嗜睡增加、工作能力下降以及肿瘤坏死因子和IL-6水平升高有关；(2)肥胖阻塞性睡眠呼吸暂停综合征患者的高细胞分裂素血症及其相关的胰岛素抵抗不能被这种疾病最常见的治疗方法，即持续气道正压治疗所逆转。此外，中和肥胖窒息患者的TNFa可显著且显著地减少EDS。在这项应用中，我们建议研究睡眠恢复、肥胖和中年对正常睡眠者在睡眠限制一周后的嗜睡、表现和炎性细胞因子的影响(特定目标1-3)。我们假设，恢复睡眠2晚并不能充分逆转轻度睡眠限制的不良影响，而肥胖和中年会增加轻度睡眠限制的不良影响。此外，我们建议测试(A)细胞因子和脂肪因子(瘦素和脂联素)以及胰岛素抵抗/内脏脂肪的24小时昼夜节律模式，在非肥胖窒息患者中，以及在体重、年龄和性别匹配的对照组中；以及(B)在交叉安慰剂对照设计(特定目标4)中使用CPAP的效果。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的IL-6、TNFa和胰岛素抵抗/内脏脂肪水平，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、肌动图、24小时采血、皮质醇、TNFa、IL-6、瘦素、脂联素和腹部CT体脂分布、CPAP和Sham CPAP。这些研究将共同为TNFa和IL-6在EDS和OSA中的作用提供更多的证据，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.