Inactivation of hyperpermeability after ischemia-reperfusion induced inflammation

缺血再灌注引起的炎症后通透性过高的失活

• 批准号: 8280359
• 负责人: Walter N. Duran
• 金额: $ 36.85万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280359
• 关键词: Adhesions; Adjuvant; Area; Attenuated; Back; Biological; Biological Testing; Blood Vessels; Cell-Cell Adhesion; Cells; Compartment syndromes; Complex; Computer-Assisted Image Analysis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Edema; Emergency Situation; Endothelial Cells; Endothelium; Equilibrium; Event; GTP-Binding Proteins; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Hetastarch; Hypoxia; Iloprost; Image Analysis; Inflammation; Inflammatory; Intervention; Investigation; Ischemia; Knowledge; Laboratories; Learning; Maintenance; Microscopy; Microvascular Permeability; Molecular; Molecular Biology; Muscle; Natural History; Nitric Oxide Synthase; Operative Surgical Procedures; Papaverine; Pathway interactions; Permeability; Phase; Physiological; Process; Property; Prostaglandins I; Proteins; Reperfusion Therapy; Reporting; Research; Role; Signal Transduction; Stress; Striated Muscles; Surgeon; System; TNF gene; Testing; Therapeutic; Time; Tissues; Tumor Necrosis Factor-alpha; Tweens; Vasodilation; Work; analog; base; clinically relevant; design; enhancing factor; feeding; in vivo; intravital microscopy; neutrophil; prevent; response; restoration

DESCRIPTION (provided by applicant): Increased microvascular permeability is a hallmark of inflammation and characterizes the initial events in ischemia-reperfusion. Previous research has focused on how to prevent the onset and the maintenance of the elevated permeability. We propose to investigate the mechanisms that inactivate hyperpermeability in the inflammatory phase of ischemia-reperfusion and return it to baseline levels in striated muscle. We hypothesize that after a hyperpermeability phase, the postischemic muscle begins a process to inactivate hyperpermeability and restore the physiological barrier properties of the microvascular wall. We further propose that Epac and Rap-1 serve as `Barrier Enhancing Factors' and participate in the hyperpermeability-inactivation process. Maintenance of microvascular barrier properties is mainly regulated through factors controlling proteins that form intercellular adhesions. Cell-cell adhesion, in turn is regulated in many cells in part through feed-back signaling between small GTP-binding proteins and junctional proteins. The Specific Aims designed to test the hypothesis are: Specific Aim 1: To investigate the timed inactivation of hyperpermeability after ischemia- reperfusion induced inflammation. Specific Aim 2: To determine whether activation of Epac/Rap-1 inactivates hyperpermeability in ischemia-reperfusion. Specific Aim 3: To test whether endothelial Epac/Rap-1 signaling is responsible for restoration of barrier integrity. We will apply microscopy, computer-assisted image analysis and molecular biology approaches in striated muscle (in vivo) and in endothelial cells to elucidate the role of these relevant cAMP-stimulated factors in the inactivating phase of hyperpermeability in postischemic muscle. We will use endothelial cells exposed to oxygenation and reoxygenation to explore the cellular mechanisms. The body response to inflammation and to ischemia reperfusion is highly complex and involves well orchestrated molecular mechanisms. Knowledge of the timing between hyperpermeability and its "physiological" inactivation in ischemia-reperfusion should provide a window of opportunity for interventions promoting inactivation of hyperpermeability to prevent excessive edema, compartment syndrome and tissue damage. Our results should be of clinical relevance to revascularization in elective and emergency vascular surgery. PUBLIC HEALTH RELEVANCE: Our results will advance current understanding of the molecular mechanisms involved in the inactivation of increased permeability. The emerging data will be clinically relevant in the settings of revascularization. The results could serve as a basis for new adjuvant therapeutic approaches to assist vascular surgeons in preventing damage and returning function to postischemic muscles.

描述（由申请人提供）：微血管通透性增加是炎症的标志，是缺血-再灌注初始事件的特征。以往的研究主要集中在如何预防通透性升高的发生和维持。我们建议研究在缺血-再灌注的炎症期使高通透性失活并使横纹肌恢复到基线水平的机制。我们推测，在高渗透性期后，缺血后肌肉开始失活高渗透性并恢复微血管壁的生理屏障特性。我们进一步提出Epac和Rap-1作为“屏障增强因子”参与了高透性失活过程。微血管屏障特性的维持主要是通过控制形成细胞间粘连的蛋白质的因子来调节的。细胞-细胞粘附，反过来在许多细胞中部分通过小gtp结合蛋白和连接蛋白之间的反馈信号进行调节。为验证这一假设，我们设计了以下的特定目的：特定目的1：研究缺血-再灌注诱导炎症后高通透性的时间失活。特异性目的2：确定Epac/Rap-1的激活是否能抑制缺血再灌注时的高通透性。特异性目的3：测试内皮细胞Epac/Rap-1信号是否负责屏障完整性的恢复。我们将应用显微镜，计算机辅助图像分析和分子生物学方法在横纹肌（体内）和内皮细胞中阐明这些相关的camp刺激因子在缺血后肌肉高渗透性失活阶段的作用。我们将使用暴露于氧化和再氧化的内皮细胞来探索细胞机制。机体对炎症和缺血再灌注的反应是高度复杂的，涉及精心安排的分子机制。了解缺血-再灌注中高渗透性及其“生理”失活之间的时间，应该为促进高渗透性失活的干预提供机会，以防止过度水肿、筋膜室综合征和组织损伤。我们的研究结果对选择性和紧急血管手术的血管重建术具有临床意义。公共卫生相关性：我们的结果将促进目前对渗透性增加失活的分子机制的理解。新出现的数据将在血运重建术中具有临床相关性。结果可作为新的辅助治疗方法的基础，以协助血管外科医生预防损伤和恢复缺血后肌肉的功能。