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: 8550745
• 负责人: MARK R OPP
• 金额: $ 29.93万
• 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/8550745
• 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）：衰老容易患病疾病的因素多种多样，复杂且不理解。败血症每年杀死美国数十万人，相关医院费用为数十亿美元。令人担忧的是，败血症的发病率每年增加8％以上。败血症被认为是老年的典型疾病，因为随着年龄的增长，严重败血症的发病率和死亡率呈指数增加。患者65岁及以上的患者占所有败血症病例的65％，并且年龄独立预测败血症死亡率。研究表明，慢性炎症有助于老年人的发病率和死亡率增加。在诱发因素中，两名因导致慢性炎症和老年人败血症的影响而被低估：睡眠碎片和血脑屏障的运输。老年人的睡眠是分散的，睡眠破坏与细胞因子的产生增加有关，包括肿瘤坏死因子（TNF）。衰老增加了率TNF从血液到脑的运输，整个血脑屏障（BBB），跨BBB运输的TNF可以诱导大脑内更多TNF的产生。这些观察结果表明，BBB转运的衰老，睡眠碎片和变化有助于慢性神经炎症。我们将在四个目标的背景下检验这一假设。我们将使用塞卡尔连接和穿刺的特征良好模型在小鼠中诱导败血症。我们将确定衰老和睡眠碎片化对败血症结果的影响（AIM 1），并量化脑和周围细胞因子谱的变化（AIM 2）。我们还将量化衰老的影响 对TNF跨BBB及其在大脑中的累积速度的速率的睡眠破碎（AIM 3）。最后，我们将抑制大脑中的细胞因子作用，并确定对败血症发病率和死亡率的影响（AIM 4）。大多数实验的结果指标包括临床疾病的症状（睡眠改变，脑温的变化，降低水和食物消耗，体重减轻）和死亡率。我们已经验证了Luminex XMAP（R）技术，用于从小鼠脑中对细胞因子的多重测定法。我们将使用这种方法来量化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。我们将确定从血液到脑的涌入率用于TNF，并确定BBB的完整性。最后，我们将直接在大脑中与TNF拮抗，并干扰TNF和其他细胞因子的转录调节。据我们所知，尚未研究衰老特征的衰老，睡眠破碎化和变化，因为尚未研究败血症结果的决定因素。该项目的完成将提供有关动态过程之间相互作用（衰老，变化的BBB参数，败血症）和诱发因素（睡眠碎片）的关键信息，这可能会导致对重症疾病或受伤的响应。