THE ROLE OF CYTOKINES IN SLEEPINESS AND SLEEP APNEA

描述(申请人摘要)：日间过度嗜睡是一种 主要的公共卫生问题，部分原因是患有EDS的个人 通常在工作中效率低下，更容易发生事故，以及 一般都不能在白天正常运作。EDS是 阻塞性睡眠呼吸暂停患者的主要表现 (OSA)，没有睡眠呼吸暂停的肥胖者经常报告。这个 在这两种类型的个体中观察到的EDS的潜在机制并不是 安全。我们最近已经证明，促炎症和 疲劳诱导细胞因子、肿瘤坏死因子-α和 在单个血浆样本中检测到的白细胞介素6(IL-6)在 EDS障碍受试者。此外，在初步研究中，我们 与瘦人相比，肥胖者这两种细胞因子升高。 受试者，睡眠障碍和肥胖都是导致 细胞因子升高。最近，我们发现白天血浆中IL-6的水平 在实验诱导的EDS中，通过使用睡眠剥夺和 晚上良好的睡眠与白天睡眠水平的降低有关 健康的年轻受试者。有一大堆文献牵涉到几个 促炎细胞因子在动物睡眠调节中的作用；然而， 关于人类睡眠的细胞因子研究一直非常有限。最基本的 拟议的研究将检验的假设是，促炎作用 细胞因子，如肿瘤坏死因子α和白介素6，与EDS相关，并可能有助于EDS的发生。我们 将通过确定昼夜节律分泌模式来检验这一假设 与EDS相关的受试者血浆中的肿瘤坏死因子α和白介素6 患有阻塞性睡眠呼吸暂停综合症或肥胖。此外，我们还将确定夜间鼻腔CPAP 降低睡眠呼吸暂停患者白天血浆中肿瘤坏死因子α和白介素6的浓度。在……里面 此外，我们将通过实验在健康的年轻受试者中诱导EDS 使用完全睡眠剥夺或一周的睡眠限制，这是模仿 现实生活中的情景，决定了模式之间的关系 日间血浆肿瘤坏死因子α和IL-6浓度与日间嗜睡 使用MSLT进行客观测量。最后，我们将评估白天的影响 健康受试者午睡对午睡后嗜睡及肿瘤坏死因子α和白介素6的影响 分泌物。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，计算机化脑电，活动记录仪， 24小时采血、24小时记录核心体温和化验 用于肿瘤坏死因子α和白介素6。这些研究将共同提供额外的 肿瘤坏死因子α和IL-6在EDS中作用的证据，并为 开发潜在的治疗干预措施。

DESCRIPTION (applicant's abstract): 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 one 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 observed in both types of these individuals are not clear. We have recently demonstrated that the pro-inflammatory and fatigue-inducing cytokines, tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6), assayed in single plasma samples, are elevated in subjects with disorders of EDS. In addition, in preliminary studies, we demonstrated that these two cytokines are elevated in obese, compared to lean subjects, and that both sleep disturbance and obesity contribute to the cytokine elevation. More recently, we showed that daytime plasma levels of IL-6 are elevated in experimentally-induced EDS by the use of sleep deprivation and that a good night's sleep is associated with decreased daytime levels in healthy young subjects. There is a large literature implicating several pro-inflammatory cytokines in the regulation of sleep in animals; however, cytokine research on sleep in humans has been very limited. The fundamental hypothesis to be tested by the proposed studies is that the pro-inflammatory cytokines, TNFalpha and IL-6, are associated with and may contribute to EDS. We will test this hypothesis by determining the circadian secretory patterns of TNFalpha and IL-6 in plasma obtained from subjects that exhibit EDS associated with OSA or obesity. Also, we will determine whether nighttime nasal CPAP reduces daytime plasma TNFalpha and IL-6 concentrations in sleep apneics. In addition, we will experimentally induce EDS in healthy young subjects by the use of total sleep deprivation or one week of sleep restriction, which mimics real life-situations, to determine the relationship between the pattern of daytime plasma TNFalpha and IL-6 concentrations and daytime sleepiness as measured objectively using MSLT. Finally, we will assess the effects of daytime napping, in healthy subjects, on post-nap sleepiness and TNFalpha and IL-6 secretion. In these studies, we will use a series of experimental techniques including nighttime polysomnography, MSLT, computerized EEG, actigraphy, 24-hour blood sampling, 24-hour recording of core body temperature, and assays for TNFalpha and IL-6. These studies collectively will provide additional evidence for a role of TNFalpha and IL-6 in EDS and lay the foundation for the development of potential therapeutic interventions.