Tissue Factor in Myocardial Reperfusion

心肌再灌注中的组织因子

基本信息

批准号：
6785318
负责人：
Jakob VINTEN-JOHANSEN
金额：
$ 38万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Tissue Factor (TF) is important in the coagulation cascade. However, TF also has pro-inflammatory effects through the generation of thrombin and subsequent activation of endothelium, myocytes, fibroblasts and pro-inflammatory cytokines via activation of protease activated receptor-1 (PAR1). The interaction between activated endothelium and neutrophils (PMNs) during the early moments of reperfusion (early phase events) is critical in the pathogenesis of endothelial dysfunction, infarction, and apoptosis during cardiac ischemia-reperfusion. The interaction between PMNs and myocytes occurs in later stages (>4 hours) of reperfusion. Furthermore, we have demonstrated that PMN's and macrophages may also contribute to both extension of infarction and to apoptosis during a late phase of reperfusion 6 to 72 hours after the onset of reperfusion. Our preliminary data show that a) TF is expressed diffusely in myocardium primarily reperfusion, and b) thrombin is a potent stimulator of PMN adhesion to endothelium, and is involved in the pathogenesis of infarction. The central hypothesis to be tested in this application is that ischemia-reperfusion stimulates expression of TF, the formation of the TF/FVIla complex and subsequent generation of thrombin (i.e. the TF-thrombin pathway). This pathway contributes to the pathogenesis of ischemia-reperfusion injury by promoting PMN- and macrophage-mediated inflammatory responses on endothelium and cardiomyocyte, as well as by promoting intravascular coagulation. The proposed studies will achieve the following specific aims 1) determine the time course of TF expression and activation of the TF-thrombin pathway during regional myocardial ischemia and reperfusion; 2) determine if the TF-thrombin pathway plays an important role in initiating PMN-mediated reperfusion injury versus intravascular coagulation in the early phase of reperfusion (0-6 hours) by PAR1-dependent and PAR1-independent mechanisms; 3) determine if TF-related activity during the late phase of reperfusion (6-72 hours) contributes to the continued recruitment of the inflammatory response and extension of reperfusion injury by PAR1-dependent and PAR1-independent mechanisms; and 4) determine if intracoronary administration of specific inhibitors of the TF-thrombin pathway attenuates reperfusion injury in a clinically relevant model of catheter-based intervention. These studies will identify a potentially new mechanism contributing to inflammatory-mediated myocardial ischemia-reperfusion injury, and will develop strategies for intracoronary therapy to attenuate ischemia-reperfusion injury in the catheterization laboratory.

描述（由申请人提供）：组织因子（TF）在凝血级联方面很重要。然而，TF还通过产生凝血酶以及随后激活内皮细胞，成肌细胞，成纤维细胞和促炎细胞因子，通过激活蛋白酶激活受体1（PAR1）具有促炎作用（PAR1）。在再灌注（早期事件）期间活化的内皮与中性粒细胞（PMN）之间的相互作用在心脏局部缺血再灌注期间内皮功能障碍，梗塞和凋亡的发病机理中至关重要。 PMN和心肌细胞之间的相互作用发生在再灌注的后期（> 4小时）。此外，我们已经证明，在再灌注发作后6至72小时的再灌注后期，PMN和巨噬细胞也可能有助于梗塞的扩展和凋亡。我们的初步数据表明，a）TF在心肌主要再灌注中散布，而b）凝血酶是对内皮的有效刺激剂，并且参与了梗塞的发病机理。在此应用中要检验的中心假设是缺血 - 重新灌注刺激TF的表达，TF/FVILA复合物的形成以及凝血酶的后续产生（即TF-凝血酶途径）。该途径通过促进内皮细胞和心肌细胞上的PMN和巨噬细胞介导的炎症反应以及促进血管内凝血来促进缺血 - 再灌注损伤的发病机理。拟议的研究将达到以下特定目的1）确定区域心肌缺血和再灌注期间TF表达的时间过程和TF-凝血酶途径的激活； 2）确定TF-凝血酶途径在通过PAR1依赖性和与PAR1独立的机制中的早期再灌注（0-6小时）中启动PMN介导的再灌注损伤与血管内凝结起着重要作用； 3）确定在再灌注后期（6-72小时）期间与TF相关的活性是否有助于继续募集炎症反应和通过PAR1依赖性和与PAR1无关机制扩展再灌注损伤； 4）确定在基于导管的干预术的临床相关模型中，冠状动脉内给药是否会减轻再灌注损伤。这些研究将确定一种潜在的新机制，这些机制导致炎症介导的心肌缺血 - 再灌注损伤，并将制定术后治疗的策略，以减轻导管实验室中衰减缺血性灌注损伤。