Despite over 300,000 cardiopulmonary bypass procedures performed each year in the US that are accompanied by gas embolism-induced cerebral dysfunction, little research is conducted today to understand molecular mechanisms of the pathological processes initiated or to develop interventions to reduce the risk of cerebral damage from gas embolism. Patient disabilities include both transient and permanent brain abnormalities such as reduced cognitive function, slurred speech, and disorientation, all of which are consistent with episodes of therapy induced stroke. At least two key triggers of gas embolism associated with bypass remain unavoidable: bubble nucleation in blood oxygenator membranes along with blood degassing triggered by rapid warming of the cooled patient blood. Through undefined molecular mechanisms, embolism bubbles promote clot formation and cellular (platelet, neutrophil, endothelial cell) activation, aggregation, and adhesion. Inflammatory pathways including complement are also activated. By defining the molecular dynamics of how blood and vessel wall biology is altered by gas emboli, as well as by identifying chemical agents that reduce 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 vitro experiments with blood components and endothelium to identify the mechanisms of gas embolism-induced changes in human blood and vascular endothelium.
Aim 2 Quantitative investigation of chemical based interventions to reduce the interactions defined in Aim 1.
Aim 3 An investigation of the mechanisms of chemical based interventions of gas emboli- blood and gas emboli-endothelial interactions under controlled and defined hemodynamic shearing conditions.
Aim 4 Development of a set of generalized computational tools for the study of multicomponent, chemical reaction dynamics of blood with deformable and growing/thrombosing bubble flowing through a deformable vessel of comparable size. Together these studies seek to provide fundamental insight into blood-and endothelium- gas emboli interactions as well as their pharmacological modulation that may eventually allow for clinical prevention or treatment of gas embolism-induced stroke, a persistent and growing health threat.
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