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Activation of clotting & cell adhesion: gas embolism

激活凝血

基本信息

批准号：
7384351
负责人：
DAVID M ECKMANN
金额：
$ 44.9万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7384351
关键词：
Address Adhesions Adsorption Affect Air Embolism Animals Attenuated Binding Biochemical Biochemical Pathway Biomimetics Blood Blood Circulation Blood Platelets Blood Vessels Blood flow Brain Brain Injuries Bypass Calcium Cardiac Cardiac Surgery procedures 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 Decompression Sickness Development Diffusion Dose Embolism Endothelial Cells Endothelium Event Functional disorder Gases Goals Health Histologic Homeostasis Human Impairment In Vitro Injury Intervention Investigation Lead Liquid substance Magnetic Resonance Imaging Measures Mechanics Medicine Membrane Oxygenators Methods Microbubbles Modeling Molecular Molecular Target Monitor Motion Neuroprotective Agents 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 Source 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 neuroprotection novel 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.

在美国，每年有30多万名体外循环患者因血管气体栓塞而导致脑功能障碍。短暂的和永久性的大脑异常都会发生。这些症状包括认知功能降低、言语和言语处理能力受损，以及定向能力减弱或迷失。所有这些都与治疗诱发中风的发作相一致。气体栓塞在医学上普遍存在，至少有两个与搭桥相关的不可避免的关键触发因素：氧合器膜中的气泡成核和冷却的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诱发损伤的关键分子机制，包括血管和血管与气泡接触时启动的病理过程。栓塞泡导致内皮细胞屏障功能紊乱、钙稳态和细胞死亡。气泡促进血栓形成、细胞激活和粘连事件。病理生理反应的分子基础的识别为治疗提供了洞察力和机会。我们的第二个研究目标是开发化学干预措施，以减少气体栓塞对组织的损伤。通过识别减弱或消除这些病理过程的化学制剂，体外血液氧合后未受调控的中风事件的风险可能得到更好的预防或控制。目的1以气体栓塞性脑损伤大鼠为模型进行体内实验，评价表面活性物质作为化学干预的剂量依赖性神经保护作用。目的2体外细胞(内皮、血小板)实验，以确定气体栓塞剂引起血管细胞功能改变的分子基础，并量化化学干预对减少脑损伤相关病理生理反应的影响(目标1)。目的3体外研究在控制和限定的仿生条件下，以化学为基础的干预与蛋白质竞争大分子表面占据气栓-血液界面。目的4对血管内气体栓塞的化学反应动力学进行数值模拟。我们试图提供对气体栓塞相关损伤的分子力学基础以及通过药物干预进行保护的基本见解。这项工作是气体栓塞性中风的神经保护的基础，中风是一种持续存在的、不断增长的健康威胁，而不进行治疗。