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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069487-04
Application #
7095849
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Massicot-Fisher, Judith
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$371,070
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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