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）：衰老导致危重疾病的因素是多种多样的，复杂的，而且还没有被很好地理解。在美国，败血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，脓毒症的发病率每年增加8%以上。脓毒症被认为是一种典型的老年疾病，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增长。65岁及以上的患者占所有败血症病例的65%，年龄独立预测败血症死亡率。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，有两个因素在导致老年人慢性炎症和败血症结果方面被低估：睡眠碎片化和血脑屏障运输。老年人的睡眠是碎片化的，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）。衰老增加了肿瘤坏死因子通过血脑屏障（BBB）从血液转运到脑的速度，而通过血脑屏障转运的肿瘤坏死因子可以诱导脑内产生更多的肿瘤坏死因子。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了慢性神经炎症。我们将在四个目标的背景下检验这一假设。我们将使用具有良好特征的盲肠结扎和穿刺模型来诱导小鼠脓毒症。我们将确定衰老和睡眠碎片化对败血症结果的影响（目的1），并量化大脑和外周细胞因子谱的变化（目的2）。我们还将量化老龄化的影响