INFLAMMATION IN THE COURSE OF EARLY MYOCARDIAL ISCHEMIA

项目1描述了细胞和分子机制， 介导急性炎症反应和组织损伤， 再灌注的先前缺血心肌在犬模型。 它 利用我们不断开发的独特模式， 我们能够：1）在心脏淋巴管插管， 短暂（1-2分钟）滞后时间进入心脏细胞外液 这使得能够在局部缺血期间进行纵向时间采样 再灌注方案。 2)通过校准多个组织样本， 关于缺血性冠状动脉血流和再灌注时间，我们可以 与组织学、免疫组织化学和分子特征相关，以及3） 利用上述，我们可以利用几个独立的战略， 测量白细胞运输作为持续时间和程度的函数 缺血时间和再灌注时间。 实验阐明了 时间关系和病理相关性 研究细胞因子诱导的分子和抗体探针， 粘附分子在体内和体外的各种细胞群中的表达。 在 此外，单克隆抗体和细胞或分子特异性 抑制剂被用来评估特定细胞的作用， 中介事件。 每个假设都由几个独立的 实验策略;总体目标与 项目2和项目3中。 这四个具体目标旨在：1）表征趋化性 介导白细胞整合素活化的信号，2）检查 白细胞内流、细胞粘附与细胞因子的关系 再灌注期间的诱导，3）检查组织和 ICAM-1和VCAM-1的可溶性形式和4）比较 长时间闭塞后再灌注期间的炎症 阐明了一小时闭塞的机制。

Project 1 characterizes the cellular and molecular mechanisms which mediate the acute inflammatory response and tissue injury ensuing upon reperfusion of the previously ischemic myocardium in a canine model. It takes advantage of a unique model which we have continually developed in which we are able to: 1) Cannulate the cardiac lymph duct so that we have access to cardiac extracellular fluid with a brief (1-2 minute) lag time which enables longitudinal temporal sampling during the ischemia reperfusion protocol. 2) By calibrating multiple tissue samples with respect to ischemic coronary blood flow and time of reperfusion we can correlate histologic, immunohistochemical, and molecular features and 3) Utilizing the above, we can exploit several independent strategies for measuring leukocyte trafficking as a function of the duration and extent of ischemia and duration of reperfusion. The experiments elucidate temporal relationships and pathological correlations by utilizing molecular and antibody probes to study induction of cytokines and adhesion molecules in various cell populations in vivo and in vitro. In addition, monoclonal antibodies and cell or molecular - specific inhibitors are utilized to evaluate the role of specific cellular mediator events. Each hypothesis is tested by several independent experimental strategies; the overall goals are highly concordant with those in projects 2 and 3. The four specific aims are designed to: 1) Characterize chemotactic signals mediating leukocyte integrin activation, 2) Examine the relationship between leukocyte influx, cell adhesion and cytokine induction during reperfusion, 3) Examine the induction of both tissue and soluble forms of ICAM-1 and VCAM-1 and 4) Compare the cell biology of inflammation during reperfusion after longer occlusion times with the mechanisms elucidated for a one hour occlusion.