Activation of clotting & cell adhesion: gas embolism

在美国，每年有超过300，000例心肺转流患者因血管气体栓塞而导致脑功能障碍。暂时性和永久性的大脑异常发生。这些包括认知功能下降，言语和言语处理障碍，以及定向力下降或丧失。所有这些都与治疗诱导的卒中发作一致。气体栓塞在医学中很普遍，至少有两个不可避免的关键触发因素与旁路相关：氧合器膜中的气泡成核和冷却患者血液快速升温引发的血液脱气。我们的研究首先旨在了解引发损伤的关键分子机制，包括血液和血管与气泡接触引起的病理过程。栓塞气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。病理生理学反应的分子基础的鉴定提供了治疗的见解和机会。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。通过识别减弱或消除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。提出了四个具体的目标：目标1在体内实验与大鼠气体栓塞诱导的脑损伤，以评估剂量依赖性神经保护使用表面活性剂作为化学为基础的干预。目的2细胞（内皮细胞、血小板）体外实验，以确定人体血液和血管中气体栓塞诱导的细胞功能变化的分子基础，并定量基于化学品的干预对减少脑损伤相关病理生理反应的影响（目的1）。目的3在受控和确定的仿生条件下，体外研究基于化学干预的气体栓塞-血液界面与蛋白质竞争大分子表面占据。目的4建立血管内气体栓塞的化学反应动力学模型。我们试图提供基本的见解气体栓塞相关的损伤以及保护的分子力学基础的药物干预。这项工作是气体栓塞诱发中风的神经保护的基础，这种中风是一种持续的，不断增长的健康威胁，如果不进行治疗。

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.