Lung-Brain Axis as a Mediator of Delirium

项目摘要/摘要 急性呼吸窘迫综合征(ARDS)是一种常见的危重疾病，其特点是严重 对直接(如病毒性肺炎)或间接、全身性(如败血症)侮辱的反应 阿龙。大多数ARDS患者会发展成神志不清，表现为急性的、波动的认知障碍。 ARDS期间的精神错乱与包括长期残疾和死亡在内的不良结局密切相关。 尽管有这样的临床意义，但ARDS中导致精神错乱的机制仍然知之甚少。 与ARDS中的妄想直接相关的一项最新科学进展是内皮细胞糖基化反应，一种 富含硫酸软骨素(CS)的层，排列在血管管腔内。在肺损伤的早期，糖衣被降解， 将大量CS释放到血液中，导致海马CS含量增加， 与精神错乱的发病机制有关的大脑区域。值得注意的是，高水平的- 危重病患者的硫酸盐化CS亚型与精神错乱的风险相关。在预赛中 实验中，我观察到这些高度硫酸盐化的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 在大脑里。这种AMPAR活性的激活可能与ARDS期间的精神错乱有关，正如我所做的那样 在肺损伤模型中观察到海马神经元兴奋性的一致性增加。 本提案中概述的工作将调查CS在AMPAR增强中的重要性 ARDS的直接形式和间接形式的神志不清的发病机制。我的工作就是确定CS是否 在肺损伤期间主要从肺内皮细胞糖基化反应释放，如果释放是 乙酰肝素酶依赖，2)确定海马区穿透CS是否导致AMPAR增加 兴奋性，以及3)确定肺内皮细胞来源的CS是否参与了肺损伤的病理生理过程。 ARDS患者通过海马神经元AMPAR增强所致的妄想症。通过这些调查，我将获得专业知识 在直接肺损伤模型中，隔离灌流肺制剂以分离和评估肺 生理学和肺内皮生物学、体外全细胞电生理学和体内 小鼠海马区的脑电图，以及与人类精神错乱有关的小鼠行为测量。 这些高度新颖的研究将使我，作为一名早期职业内科医生兼科学家，开发出一种独特的 专门研究精神错乱的肺-脑轴，同时为未来产生必要的初步数据 独立研究奖(如R01)。

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).