Reperfusion dependent events in ventricular repair

项目1是HL 42550的一个正在进行的项目，该项目在历史上利用犬的慢性缺血和再灌注模型来表征梗死心肌再灌注后的强烈炎症反应。该模型的独特特征包括心脏淋巴管插管，其允许收集细胞外液，为体外细胞生物学实验提供基于体内的试剂。我们还利用针对缺血程度校准的组织样本来定位和定量mRNA和蛋白质。开发了使用分离细胞的体外模型，以纳入体内观察到的特征并更好地描述机制。利用这些策略，我们提出了一个模型的细胞和分子机制与白细胞趋化性，再灌注后心肌损伤，并产生炎症级联反应的生长因子和细胞因子，我们建议是重要的促进组织修复诱导再灌注。这种矛盾通常保护健康组织免受炎性损伤以及炎性细胞和基于炎性的介质在组织修复和细胞保护中的细胞和分子作用。这是并一直是该计划项目赠款的长期目标;每个项目都与这些问题有关。项目1将扩展在当前资助期内进行的三项观察，这些观察研究了再灌注依赖事件的细胞和分子机制以及潜在作用。1)浸润再灌注梗死的中性粒细胞转变为纤维化和血管生成刺激的主要早期来源。2)心肌梗死再灌注后肥大细胞前体的早期吸引和数量增加及其在心室修复中的作用。3)小静脉内皮细胞中重要趋化因子的快速再灌注依赖性诱导及其对白细胞运输和血管生成的下游影响。

Project 1 is an ongoing project of HL 42550 which, historically, utilized a chronic model of ischemia and reperfusion in the dog to characterize the robust inflammatory reaction ensuring upon reperfusion of the infarcted myocardium. The unique features of this model including cannulation of the cardiac lymph duct which allowed collection of extracellular fluid providing an in vivo based reagent for in vitro cell biological experiments. We also utilized tissue samples calibrated for degree of ischemia to localize and quantitate mRNA and protein. In vitro models using isolated cells were developed to incorporate the features observed in vivo and better delineate mechanisms. Utilizing these strategies, we proposed a model of the cellular and molecular mechanisms associated with leukocyte chemotaxis, post-reperfusion myocardial injury, and a generation of inflammatory cascade of growth factors and cytokines that we proposes to be important in the facilitation of tissue repair induced by reperfusion. This paradox of that ordinarily protect healthy tissue from inflammatory injury and the cellular and molecular roles of inflammatory cells and inflammatory based mediators in tissue repair and cytoprotection. This is and has been the long-term goal of this program project grant; each of the Projects relates to these issues. Project 1 will expand on three observations made in the current grant period that examine the cellular and molecular mechanisms and potential roles of reperfusion dependent events. 1) Transition of neutrophils infiltrating the reperfused infarct to the major early source of fibrogenic and angiogenic stimuli. 2) Early attraction of mast cell precursors and increase in mast cell number in the reperfused infarct and its role in ventricular repair. 3) Rapid reperfusion-dependent induction of important chemokines in the venular endothelium and its downstream consequences with regard to leukocyte trafficking and angiogenesis.