Sepsis Outcomes and Aging: Role of Sleep Disruption and the Blood Brain Barrier

脓毒症结果和衰老：睡眠中断和血脑屏障的作用

• 批准号: 8718968
• 负责人: MARK R OPP
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718968
• 关键词: Accounting; Admission activity; Adult; Age; Aged, 80 and over; Aging; Aging-Related Process; American; Animals; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Circulation; Body Weight decreased; Brain; Brain Stem; Brain region; Cause of Death; Censuses; Characteristics; Chronic; Clinical; Communication; Complex; Critical Care; Critical Illness; Development; Disease; Elderly; Exposure to; Functional disorder; Hippocampus (Brain); Hospital Costs; Hospitals; Hypothalamic structure; Incidence; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knowledge; Laboratory mice; Ligation; Longevity; Modeling; Morbidity - disease rate; Mus; Neuraxis; Neuroglia; Older Population; Outcome; Outcome Measure; Patients; Peripheral; Plasma; Predisposing Factor; Process; Production; Protocols documentation; Puncture procedure; Reporting; Role; Sepsis; Sepsis Syndrome; Septic Shock; Sleep; Sleep Disorders; Sleep Fragmentations; Societies; Symptoms; Technology; Temperature; Testing; Therapeutic Intervention; Time; Transcriptional Regulation; Trauma; Tumor Necrosis Factor-alpha; United States National Center for Health Statistics; Water consumption; adverse outcome; age effect; aged; cytokine; food consumption; killings; mortality; neuroinflammation; research study; response; sleep regulation; young adult

DESCRIPTION (provided by applicant): The factors by which aging predisposes to critical illness are varied, complex, and not well understood. Sepsis annually kills hundreds of thousands of people in the US with associated hospital costs of billions of dollars. Of concern, sepsis incidence is increasing at more than 8% annually. Sepsis is considered a quintessential disease of old age because the incidence and mortality of severe sepsis increases exponentially as we age. Patients 65 and older account for 65% of all sepsis cases and age independently predicts sepsis mortality. Studies suggest that chronic inflammation contributes to increased morbidity and mortality in older adults. Among predisposing factors, two are underappreciated as contributing to chronic inflammation and sepsis outcomes in older adults: sleep fragmentation and blood brain barrier transport. Sleep of older adults is fragmented, and sleep disruption is associated with increased production of cytokines, including tumor necrosis factor (TNF). Aging increases the rate TNF is transported from blood-to-brain across the blood brain barrier (BBB), and TNF transported across the BBB can induce the production of more TNF within the brain. These observations suggest the intriguing hypothesis that aging, sleep fragmentation and alterations in BBB transport synergistically contribute to chronic neuroinflammation. We will test this hypothesis within the context of four Aims. We will use the well-characterized model of cecal ligation and puncture to induce sepsis in mice. We will determine the impact of aging and sleep fragmentation on sepsis outcomes (Aim 1) and quantify changes in cytokine profiles in brain and periphery (Aim 2). We will also quantify effects of aging and sleep fragmentation on the rate of TNF transport across the BBB and its accumulation in brain (Aim 3). Finally, we will inhibit cytokine actions in brain and determine effects on sepsis morbidity and mortality (Aim 4). Outcome measures for most experiments include symptoms of clinical illness (altered sleep, changes in brain temperature, reductions in water and food consumption, loss of body weight) and mortality. We have validated Luminex xMAP(R) technology for multiplex assay of cytokines from mouse brain. We will use this approach to quantify cytokine profiles in plasma and discrete brain regions (hypothalamus, hippocampus, brain stem) from the same animal. We will determine influx rates from blood-to-brain for TNF and ascertain the integrity of the BBB. Finally, we will antagonize TNF directly in brain and interfere with transcriptional regulation of TNF and other cytokines. To our knowledge, effects of aging, sleep fragmentation and alterations in BBB characteristics as determinants of sepsis outcomes have not been studied. Completion of this project will provide critical information that is currently lacking with respect to interactions among dynamic processes (aging, altered BBB parameters, sepsis) and predisposing factors (sleep fragmentation) that may contribute to negative outcomes in response to critical illness or injury.

描述（由申请人提供）：衰老易患危重病的因素多种多样，复杂，而且还没有得到很好的理解。败血症每年在美国造成数十万人死亡，相关的医院费用高达数十亿美元。值得关注的是，脓毒症的发病率每年增加超过8%。脓毒症被认为是典型的老年疾病，因为严重脓毒症的发病率和死亡率随着年龄的增长呈指数级增加。65岁及以上的患者占所有脓毒症病例的65%，年龄独立预测脓毒症死亡率。研究表明，慢性炎症导致老年人发病率和死亡率增加。在诱发因素中，有两个因素被低估为老年人慢性炎症和脓毒症的原因：睡眠碎片和血脑屏障转运。老年人的睡眠是支离破碎的，睡眠中断与细胞因子的产生增加有关，包括肿瘤坏死因子（TNF）。衰老增加了TNF从血液穿过血脑屏障（BBB）转运到脑的速率，并且穿过BBB转运的TNF可以诱导脑内产生更多的TNF。这些观察结果表明了一个有趣的假设，即衰老、睡眠片段化和BBB转运的改变协同作用导致慢性神经炎症。我们将在四个目标的背景下检验这一假设。我们将使用盲肠结扎和穿孔的良好表征的模型来诱导小鼠中的脓毒症。我们将确定衰老和睡眠片段对脓毒症结局的影响（目标1），并量化脑和外周细胞因子谱的变化（目标2）。我们还将量化衰老的影响 和睡眠片段化对TNF穿过BBB的速率及其在脑中的积累的影响（目的3）。最后，我们将抑制脑中的细胞因子作用，并确定对脓毒症发病率和死亡率的影响（目的4）。大多数实验的结果测量包括临床疾病的症状（睡眠改变，脑温变化，水和食物消耗减少，体重减轻）和死亡率。我们已经验证了Luminex xMAP（R）技术用于小鼠脑细胞因子的多重测定。我们将使用这种方法来定量来自同一动物的血浆和离散脑区域（下丘脑、海马、脑干）中的细胞因子谱。我们将确定TNF从血液到大脑的流入率，并确定BBB的完整性。最后，我们将直接在脑中拮抗TNF并干扰TNF和其他细胞因子的转录调节。据我们所知，年龄的影响，睡眠片段和血脑屏障特征的改变作为脓毒症的结果的决定因素还没有被研究。该项目的完成将提供目前缺乏的关于动态过程（衰老，BBB参数改变，败血症）和诱发因素（睡眠碎片）之间的相互作用的关键信息，这些因素可能会导致严重疾病或损伤的负面结果。