Activation of Clotting & cell adhesion : gas embolism

尽管美国每年有超过30万例体外循环手术伴有气体栓塞引起的脑功能障碍，但目前很少有研究来了解所启动的病理过程的分子机制或开发干预措施以降低气体栓塞引起脑损伤的风险。患者残疾包括暂时性和永久性脑异常，如认知功能减退、言语不清和定向障碍，所有这些都与治疗性中风发作相一致。至少有两个与旁路相关的气体栓塞的关键触发因素是不可避免的：血液氧合器膜上的气泡成核以及由冷却的患者血液快速升温引发的血液脱气。通过不明确的分子机制，栓塞泡促进凝块形成和细胞（血小板、中性粒细胞、内皮细胞）的活化、聚集和粘附。包括补体在内的炎症途径也被激活。通过定义气体栓塞如何改变血液和血管壁生物学的分子动力学，以及通过识别减少这些病理过程的化学制剂，体外血氧合后不调节卒中事件的风险可能更好地预防或控制。本研究提出了以下四个具体目标：目的1：通过体外血液成分和内皮细胞实验，确定气体栓塞诱导的人血液和血管内皮细胞变化的机制。目的2：定量研究基于化学的干预措施，以减少目的1中定义的相互作用。目的3：在可控的、明确的血流动力学剪切条件下，研究化学干预气体栓塞-血液和气体栓塞-内皮相互作用的机制。目的4：开发一套通用计算工具，用于研究具有可变形和生长/血栓形成气泡的血液的多组分化学反应动力学，这些气泡流经大小相当的可变形血管。总之，这些研究试图为血液和内皮细胞-气体栓塞的相互作用以及它们的药理学调节提供基本的见解，这些药理调节可能最终允许临床预防或治疗气体栓塞引起的中风，这是一种持续和不断增长的健康威胁。

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.