Vascular gas embolism contributes to cerebral dysfunction in over 300,000 cardiopulmonary bypass patients in the US annually. Transient and permanent brain abnormalities occur. These include reduced cognitive function, speech and speech processing impairment, and diminished or lost orientation. All are consistent with episodes of therapy-induced stroke. Gas embolism is pervasive in medicine, with at least two unavoidable key triggers associated with bypass: bubble nucleation in oxygenator membranes and blood degassing triggered by rapid warming of cooled patient blood. Our research is first directed at developing an understanding of the key, as yet undefined, molecular mechanisms inciting injury, including the initiation of pathological processes in response to blood and blood vessel contact with gas bubbles. Embolism bubbles induce derangements of endothelial cell barrier function, calcium homeostasis and cell death. Bubbles promote clot formation, cellular activation, and adhesion events. Identification of the molecular basis of pathophysiological responses provides insights and opportunities for therapy. Our second research goal is to develop chemical interventions to reduce tissue injury from gas embolism. By identifying chemical agents that attenuate or eliminate these pathological processes, the risks of unregulated stroke events after extracorporeal blood oxygenation may be better prevented or controlled.
Four specific aims are proposed:
Aim 1 In vivo experiments with rats having gas embolism-induced brain injury to evaluate dose-dependent neuroprotection using a surfactant as a chemical based intervention.
Aim 2 In vitro experiments with cells (endothelium, platelets) to identify the molecular basis of gas embolism-induced changes in cellular function in human blood and blood vessels and to quantitate effects of a chemical based intervention to reduce pathophysiological responses associated with brain injury (Aim 1).
Aim 3 In vitro investigation of a chemical based intervention in competition with proteins for macromolecular surface occupancy of gas emboli-blood interfaces under controlled and defined biomimetic conditions.
Aim 4 Computationally model chemical reaction dynamics of intravascular gas embolism. We seek to provide fundamental insights into the molecular-mechanical basis of gas embolism related injury as well as protection by pharmacological intervention. This work is the basis for neuroprotection in gas embolism-induced stroke, a persistent, growing health threat without treatment.
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