Activation of clotting & cell adhesion: gas embolism

激活凝血

基本信息

批准号：
7851187
负责人：
DAVID M ECKMANN
金额：
$ 45.82万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7851187
关键词：
Address Adhesions Adsorption Affect Air Embolism Animals Attenuated Binding Biochemical Pathway Biomimetics Blood Blood Platelets Blood Vessels Blood flow Brain Brain Injuries Bypass Calcium Cardiac Cardiopulmonary Bypass Cell Adhesion Cell Culture Techniques Cell Death Cell Death Signaling Process Cell membrane Cell physiology Cell surface Cells Cerebral Ischemia Cerebrum Chemical Agents Chemicals Coagulation Process Convection Data Decompression Sickness Diffusion Dose Embolism Endothelial Cells Endothelium Event Functional disorder Gases Goals Health Histologic Homeostasis Human Impairment In Vitro Injury Intervention Investigation Kinetics Lead Liquid substance Magnetic Resonance Imaging Measures Mechanics Medicine Membrane Oxygenators Methods Microbubbles Modeling Molecular Molecular Target Monitor Motion Nitric Oxide Operative Surgical Procedures Outcome Pathologic Processes Pathway interactions Patients Plasma Plasma Cells Platelet Activation Platelet aggregation Production Proteins Rattus Recovery Research Risk Saline Shapes Signal Pathway Signal Transduction Solutions Speech Stroke Surface Testing Therapeutic Embolization Tissues Variant Weight Work absorption advanced simulation base cell injury cellular transduction cerebrovascular chemical reaction cognitive function in vivo insight interfacial macromolecule mathematical model models and simulation neuroprotection prevent protective effect research study response shear stress simulation speech processing surfactant

项目摘要

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.

每年在美国300,000多名心肺旁路患者中，血管气体栓塞有助于脑功能障碍。瞬态和永久性大脑异常。这些包括降低认知功能，语音和语音处理障碍，以及减少或失去方向。所有这些都与治疗引起的中风发作一致。气体栓塞在医学上普遍存在，至少有两个与旁路相关的不可避免的关键触发因素：氧合膜中的气泡成核和血液脱气是由冷却的患者血液快速变暖引发的。我们的研究首先是针对对钥匙的理解的，因为尚未定义的分子机制煽动了损伤，包括响应血液和血管与气泡接触的病理过程。栓塞气泡会引起内皮细胞屏障功能，钙稳态和细胞死亡的扰动。气泡促进凝块形成，细胞活化和粘附事件。鉴定病理生理反应的分子基础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，以减少气体栓塞的组织损伤。通过鉴定减弱或消除这些病理过程的化学药物，可以更好地预防或控制体外血液氧合后不受监管的中风事件的风险。提出了四个具体目的：AIM 1在体内实验具有气体栓塞诱导的脑损伤的大鼠，以使用表面活性剂作为基于化学的干预措施评估剂量依赖性神经保护作用。 AIM 2在体外对细胞（内皮，血小板）进行体外实验，以鉴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，并定量基于化学的干预措施以减少与脑损伤相关的病理生理反应的影响（AIM 1）。 AIM 3在受控和定义的仿生条件下，在与蛋白质竞争的基于化学干预的体外研究。 AIM 4计算模拟血管内气体栓塞的化学反应动力学。我们试图提供有关与气体栓塞相关损伤的分子机械基础以及药理干预保护的基本见解。这项工作是气体栓塞引起的中风中神经保护的基础，这是一种持续的，不断增长的健康威胁，而无需治疗。