Activation of Clotting & cell adhesion : gas embolism

尽管在美国每年进行超过30万例伴有气体栓塞诱导的脑功能障碍的心肺转流手术，但目前很少进行研究来了解所引发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的脑损伤风险。 患者残疾包括短暂性和永久性脑异常，如认知功能降低、言语不清和定向障碍，所有这些都与治疗诱导的卒中事件一致。 与旁路相关的气体栓塞的至少两个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沿着由冷却的患者血液快速升温触发的血液脱气。通过不确定的分子机制，栓塞气泡促进凝块形成和细胞（血小板、中性粒细胞、内皮细胞）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试剂，可以更好地预防或控制体外血液氧合后不受管制的卒中事件的风险。 本研究的主要目的有四：目的1通过体外实验研究气体栓塞对血液成分和血管内皮细胞的影响，探讨气体栓塞对血液和血管内皮细胞的影响机制。 目标2定量研究化学干预措施，以减少目标1中定义的相互作用。 目的3在受控和确定的血流动力学剪切条件下，研究气体栓塞-血液和气体栓塞-内皮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，用于研究血液的多组分化学反应动力学，可变形和生长/血栓形成气泡流过可变形血管的可比尺寸。 这些研究旨在为血液和内皮-气体栓塞相互作用及其药理学调节提供基本见解，最终可能允许临床预防或治疗气体栓塞诱导的卒中，这是一种持续且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.