Reperfusion dependent events in ventricular repair

项目1是HL 42550的一个正在进行的项目，从历史上看，该项目利用狗的慢性缺血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的插管，允许收集细胞外液，为体外细胞生物学实验提供体内试剂。我们还利用组织样本校准的缺血程度，以定位和定量mRNA和蛋白质。利用分离细胞建立的体外模型纳入了在体内观察到的特征，并更好地描述了机制。利用这些策略，我们提出了一个与白细胞趋化性、再灌注后心肌损伤以及生长因子和细胞因子炎症级联产生相关的细胞和分子机制模型，我们认为这些机制在促进再灌注诱导的组织修复中很重要。这一悖论通常保护健康组织免受炎症损伤，炎症细胞和炎症介质在组织修复和细胞保护中的细胞和分子作用。这一直是这个项目拨款的长期目标；每个项目都与这些问题有关。项目1将扩展在当前拨款期间所做的三个观察，研究再灌注依赖事件的细胞和分子机制和潜在作用。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)再灌注梗死中肥大细胞前体的早期吸引和肥大细胞数量的增加及其在心室修复中的作用。静脉内皮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.