Lung-Brain Axis as a Mediator of Delirium

肺脑轴作为谵妄的中介

• 批准号: 10283811
• 负责人: Joseph Alan Hippensteel
• 金额: $ 16.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283811
• 关键词: Acids; Acute; Adult Respiratory Distress Syndrome; Award; Behavioral Assay; Benzodiazepines; Beta-glucuronidase; Biological; Biology; Blood Circulation; Blood Vessels; Brain; Brain region; Cells; Cessation of life; Chemosensitization; Chondroitin ABC Lyase; Chondroitin Sulfate A; Chondroitin Sulfates; Cleaved cell; Clinical; Conscious; Critical Illness; Data; Delirium; Early Mobilizations; Electroencephalography; Electrophysiology (science); Endothelial Cells; Endothelium; Excision; Extravasation; Fostering; Functional disorder; Funding; Future; Glycocalyx; Glycosaminoglycans; Heparitin Sulfate; Hippocampus (Brain); Homeostasis; Human; Hyperactivity; Hypoxemia; Hypoxia; Impaired cognition; Inflammatory; Intervention; Invaded; Investigation; Ion Channel; Knockout Mice; Laboratories; Lead; Lung; Lung Inflammation; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Modification; Mus; Neurons; Outcome; Pathogenesis; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Physicians; Physiology; Plasma; Play; Pre-Clinical Model; Preparation; Research; Risk; Role; Scientific Advances and Accomplishments; Scientist; Sepsis; Slice; Source; Survivors; Technical Expertise; Techniques; Time; Up-Regulation; Viral Pneumonia; Whole Organism; Work; analog; base; behavior measurement; career; clinically relevant; clinically significant; cohort; disability; experimental study; heparanase; in vivo; in vivo Model; inhibitor/antagonist; lung injury; mouse model; neuronal excitability; novel; receptor; response; success; sugar; targeted treatment; translational study; vascular bed

Project Summary/Abstract The Acute Respiratory Distress Syndrome (ARDS) is a common critical illness characterized by severe hypoxemia in response to either direct (e.g. viral pneumonia) or indirect, systemic (e.g. sepsis) insults to the lung. Most patients with ARDS will develop delirium, defined by acute, fluctuating disturbances in cognition. Delirium during ARDS is strongly associated with poor outcomes including long-term disability and death. Despite this clinical significance, the mechanisms responsible for delirium in ARDS remain poorly understood. One recent scientific advance with direct relevance to delirium in ARDS is the endothelial glycocalyx, a chondroitin sulfate (CS)-rich layer that lines the vascular lumen. The glycocalyx is degraded early in lung injury, releasing large concentrations of CS into the bloodstream with resultant increases in hippocampal CS content, a brain region implicated in delirium pathogenesis. Remarkably, the presence of elevated levels of highly- sulfated CS subtypes in humans with critical illness is associated with risk of delirium. In preliminary experiments, I observed that these same highly-sulfated CS subtypes can directly potentiate the activity of α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), the primary excitatory ion channel in the brain. This activation of AMPAR activity may be biologically relevant to delirium during ARDS, as I have observed concordant increases in neuronal excitability in the hippocampi in a lung injury model. The work outlined in this proposal will investigate the importance of AMPAR potentiation by CS in the pathogenesis of delirium in both direct and indirect forms of ARDS. My work seeks to 1) determine if CS is predominantly released from the pulmonary endothelial glycocalyx during lung injury and if release is heparanase-dependent, 2) determine if hippocampal-penetrating CS is responsible for increased AMPAR excitability, and 3) determine whether pulmonary-endothelium derived CS contributes to the pathophysiology of delirium in ARDS through hippocampal AMPAR potentiation. Through these investigations, I will gain expertise in modeling of direct lung injury, isolated perfused lung preparations to isolate and assess pulmonary physiology and pulmonary endothelial biology, ex vivo whole-cell electrophysiology and in vivo electroencephalography in murine hippocampi, and a murine behavioral measure relevant to human delirium. These highly-novel studies will allow me, as an early career physician-scientist, to develop a unique expertise studying the lung-brain axis in delirium, while generating essential preliminary data for future independent research awards (e.g. R01).

项目总结/摘要 急性呼吸窘迫综合征（Acute Respiratory Distress Syndrome，ARDS）是一种常见的危重病， 对直接（如病毒性肺炎）或间接全身性（如败血症）损伤的低氧血症 肺。大多数ARDS患者会出现谵妄，表现为急性波动性认知障碍。 ARDS期间的谵妄与不良结局（包括长期残疾和死亡）密切相关。 尽管有这种临床意义，但对ARDS中谵妄的机制仍知之甚少。 一项与ARDS谵妄直接相关的最新科学进展是内皮糖萼， 硫酸软骨素（CS）丰富的层，内衬血管腔。糖萼在肺损伤早期被降解， 将大量CS释放到血流中，导致海马CS含量增加， 与谵妄发病机制有关的大脑区域。值得注意的是，高水平的- 患有危重病的人中硫酸化CS亚型与谵妄的风险相关。初步 实验中，我观察到这些相同的高度硫酸化CS亚型可以直接增强α- 氨基-3-羟基-5-甲基-4-异恶唑丙酸 酸 受体（AMPAR），主要的兴奋性离子通道 在大脑中。这种AMPAR活性的激活可能与ARDS期间的谵妄具有生物学相关性，正如我所做的那样。 在肺损伤模型中观察到肺动脉中神经元兴奋性的一致增加。 本提案中概述的工作将调查CS在AMPAR增强中的重要性。 在ARDS的直接和间接形式中谵妄的发病机制。我的工作旨在确定CS是否是 在肺损伤期间主要从肺内皮糖萼释放，如果释放是 乙酰肝素酶依赖性，2）确定是否是导致AMPAR增加的原因 兴奋性，以及3）确定肺内皮衍生的CS是否有助于 通过海马AMPAR增强作用引起的ARDS谵妄。通过这些调查，我将获得专业知识 在直接肺损伤模型中，分离灌注肺制剂以分离和评估肺损伤。 生理学和肺内皮生物学，离体全细胞电生理学和体内 在小鼠脑电描记术，以及与人类谵妄相关的小鼠行为测量。 这些高度新颖的研究将使我，作为一个早期的职业医生科学家，开发一个独特的 专门研究谵妄中的肺脑轴，同时为未来的研究提供必要的初步数据。 独立研究奖（如R 01）。