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: 8413593
• 负责人: MARK R OPP
• 金额: $ 30.56万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413593
• 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. PUBLIC HEALTH RELEVANCE: Sepsis is the number 1 non-cardiac killer in hospitals and is particularly lethal in adults aged 65 and over. The reason why aging is associated with increased mortality in older adults is not well understood. We hypothesize that sleep problems in older adults produce inflammation, which in turn alters the ability of the brain to respond appropriately and predisposes patients to adverse sepsis outcomes. These sleep problems before the onset of sepsis are compounded by the severe sleep disruption that occurs while patients are in the ICU.

描述（由申请人提供）：衰老导致危重疾病的因素多种多样、复杂且尚未被充分理解。在美国，脓毒症每年导致数十万人死亡，相关的医院费用高达数十亿美元。值得关注的是，脓毒症发病率每年以超过 8% 的速度增加。脓毒症被认为是一种典型的老年疾病，因为随着年龄的增长，严重脓毒症的发病率和死亡率呈指数级增加。 65 岁及以上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，慢性炎症会增加老年人的发病率和死亡率。在诱发因素中，有两个因素被低估了，它们是导致老年人慢性炎症和败血症结果的因素：睡眠碎片化和血脑屏障转运。老年人的睡眠是碎片化的，睡眠中断与细胞因子（包括肿瘤坏死因子（TNF））产生的增加有关。衰老会增加 TNF 穿过血脑屏障 (BBB) 从血液转运至大脑的速度，而 TNF 穿过 BBB 转运可诱导大脑内产生更多 TNF。这些观察结果提出了一个有趣的假设，即衰老、睡眠碎片化和血脑屏障运输的改变协同促进慢性神经炎症。我们将在四个目标的背景下检验这一假设。我们将使用充分表征的盲肠结扎和穿刺模型来诱导小鼠败血症。我们将确定衰老和睡眠碎片化对脓毒症结局的影响（目标 1），并量化大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 睡眠碎片化对 TNF 穿过 BBB 的转运率及其在大脑中的积累的影响（目标 3）。最后，我们将抑制大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（目标 4）。大多数实验的结果指标包括临床疾病症状（睡眠改变、脑温度变化、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) 技术可用于小鼠大脑细胞因子的多重检测。我们将使用这种方法来量化同一动物血浆和离散大脑区域（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，并确定血脑屏障的完整性。最后，我们将直接在大脑中拮抗TNF，干扰TNF和其他细胞因子的转录调节。据我们所知，衰老、睡眠碎片化和血脑屏障特征改变作为败血症结果的决定因素的影响尚未得到研究。该项目的完成将提供目前缺乏的关于动态过程（衰老、血脑屏障参数改变、脓毒症）和诱发因素（睡眠碎片化）之间相互作用的关键信息，这些信息可能导致危重疾病或损伤产生负面结果。 公共卫生相关性：脓毒症是医院中排名第一的非心脏杀手，对于 65 岁及以上的成年人尤其致命。衰老与老年人死亡率增加相关的原因尚不清楚。我们假设老年人的睡眠问题会产生炎症，进而改变大脑适当反应的能力，并使患者容易出现脓毒症的不良后果。脓毒症发作前的这些睡眠问题因患者在 ICU 期间发生的严重睡眠中断而变得更加复杂。