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: 7858342
• 负责人: Walter N. Duran
• 金额: $ 39万
• 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/7858342
• 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; Hand; 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; 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; public health relevance; 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。先前的研究主要集中在如何预防渗透性升高的发生和维持。我们建议研究在缺血再灌注炎症阶段使高渗透性失活并将其恢复到横纹肌基线水平的机制。我们假设，在渗透性过高阶段之后，缺血后肌肉开始一个使渗透性过高失活并恢复微血管壁的生理屏障特性的过程。我们进一步提出 Epac 和 Rap-1 作为“屏障增强因子”并参与通透性过高失活过程。微血管屏障特性的维持主要通过控制形成细胞间粘附的蛋白质的因子来调节。细胞间粘附反过来在许多细胞中部分地通过小 GTP 结合蛋白和连接蛋白之间的反馈信号进行调节。旨在检验该假设的具体目标是： 具体目标 1：研究缺血再灌注引起的炎症后通透性过高的定时失活。具体目标 2：确定 Epac/Rap-1 的激活是否会抑制缺血再灌注中的高通透性。具体目标 3：测试内皮 Epac/Rap-1 信号传导是否负责屏障完整性的恢复。我们将在横纹肌（体内）和内皮细胞中应用显微镜、计算机辅助图像分析和分子生物学方法，以阐明这些相关的 cAMP 刺激因子在缺血后肌肉通透性过高失活阶段中的作用。我们将使用暴露于氧合和再氧合的内皮细胞来探索细胞机制。身体对炎症和缺血再灌注的反应非常复杂，涉及精心策划的分子机制。了解缺血再灌注过程中通透性过高与其“生理”失活之间的时间关系应该为促进通透性过高失活的干预措施提供机会，以防止过度水肿、骨筋膜室综合征和组织损伤。我们的结果应该与择期和急诊血管手术中的血运重建具有临床相关性。公共健康相关性：我们的结果将促进目前对通透性增加失活分子机制的理解。新出现的数据将在血运重建方面具有临床意义。研究结果可以作为新辅助治疗方法的基础，帮助血管外科医生预防缺血后肌肉损伤并恢复其功能。