Activation of clotting & cell adhesion: gas embolism

在美国，每年有超过30万例体外循环患者因血管气体栓塞导致脑功能障碍。会发生暂时性和永久性的脑部异常。这些症状包括认知功能减退、言语和言语处理障碍、方向感减退或丧失。都与治疗性中风发作相符。气体栓塞在医学上是普遍存在的，至少有两个不可避免的关键触发因素与旁路相关：氧合器膜上的气泡成核和冷却患者血液快速升温引发的血液脱气。我们的研究首先是针对关键的，尚未定义的，刺激损伤的分子机制的理解，包括响应血液和血管与气泡接触的病理过程的启动。栓塞泡诱导内皮细胞屏障功能紊乱、钙稳态和细胞死亡。气泡促进凝块形成、细胞活化和粘附事件。病理生理反应的分子基础的鉴定为治疗提供了见解和机会。我们的第二个研究目标是开发化学干预措施，以减少气体栓塞造成的组织损伤。通过识别能够减弱或消除这些病理过程的化学制剂，体外血氧合后发生不调节卒中事件的风险可能会得到更好的预防或控制。提出了四个具体目的：目的1：用气体栓塞性脑损伤大鼠进行体内实验，评估表面活性剂作为化学干预的剂量依赖性神经保护作用。目的2：利用细胞（内皮、血小板）进行体外实验，以确定气体栓塞诱导的人体血液和血管细胞功能改变的分子基础，并量化化学干预减少脑损伤相关病理生理反应的效果（目的1）。目的3：体外研究在受控和定义的仿生条件下，化学干预与蛋白质竞争，使气体栓塞-血液界面的大分子表面占据。目的4建立血管内气体栓塞的化学反应动力学模型。我们寻求对气体栓塞相关损伤的分子力学基础以及药物干预的保护提供基本的见解。这项工作是气体栓塞性中风的神经保护的基础，这是一种持续的、不断增长的健康威胁，没有治疗。

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.