Lung-Brain Axis as a Mediator of Delirium
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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).
