Activation of Clotting & cell adhesion : gas embolism

尽管美国每年进行的30多万例体外循环手术伴随着气体栓塞引起的脑功能障碍，但目前很少有研究了解气体栓塞引发的病理过程的分子机制，或开发干预措施来降低气体栓塞导致的脑损伤风险。患者的残疾包括暂时性和永久性的大脑异常，如认知功能降低、说话含糊和定向障碍，所有这些都与治疗引起的中风发作一致。至少有两个与搭桥相关的气体栓塞的关键触发因素仍然是不可避免的：血液氧合器膜中的气泡成核以及冷却的患者血液快速升温引发的血液脱气。栓塞泡通过未明确的分子机制促进血栓的形成和细胞(血小板、中性粒细胞、内皮细胞)的激活、聚集和粘连。包括补体在内的炎症途径也被激活。通过定义气体栓子如何改变血液和血管壁生物的分子动力学，以及通过识别减少这些病理过程的化学物质，体外血液氧合后未受控制的中风事件的风险可能被更好地预防或控制。目的1通过血液成分和血管内皮细胞的体外实验，探讨气体栓塞剂对人体血液和血管内皮细胞的影响机制。目的2定量研究化学干预以减少目标1中定义的相互作用。目的3研究在控制和限定的血流动力学剪切条件下，气体栓子-血液和气体栓子-血管内皮细胞相互作用的化学干预机制。目的4开发一套通用的计算工具，用于研究具有可变形和生长/血栓形成的气泡流过同等大小的可变形血管的血液的多组分化学反应动力学。总之，这些研究试图为血液和内皮-气体栓子的相互作用以及它们的药理调节提供基本的见解，最终可能允许临床预防或治疗气体栓塞引起的中风，这是一种持续且日益增长的健康威胁。

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.