Gram-negative sepsis is a major cause of death in intensive care units in the United States. Sepsis is induced by the presence of pathogenic bacteria in the blood. Monocytes of the host innate immune system orchestrate a rapid response to bacterial lipopolysaccharide (LPS [endotoxin]) by expressing various cytokines and by expressing the procoagulant protein tissue factor (TF), which initiates disseminated intravascular coagulation. Recent studies indicate that administration of anticoagulants reduces mortality in patients with severe sepsis. The long-term objectives of this proposal are to elucidate the mechanism by which coagulation proteases contribute to inflammation during sepsis. Our central hypothesis is that FXa activation of protease activated receptor 2 (PAR-2) enhances IL-6 expression and increases lethality during sepsis. We will also determine the role of thrombin (FIIa) -PAR- 1 signaling in sepsis. We will employ selective inhibitors of FXa and FIIa and analyze PAR-1- and PAR-2-dependent mice in a lethal mouse model of sepsis. In addition, we will use bone marrow transplantation to determine the role of TF and PAR-1 expression on monocytes versus endothelial cells in sepsis. Finally, we will generate mice that constitutively or inducibly express PAR-2 in endothelial cells to directly test our central hypothesis that PAR-2 is a key component of a pathogenic pathway involved in lethal sepsis. These studies should define the mechanism by which coagulation proteases enhance inflammation during sepsis. The clinical relevance of these studies is that they may provide new insight that can be used to develop improved therapeutic strategies for the treatment of patients with severe sepsis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048872-11
Application #
6623709
Study Section
Pathology A Study Section (PTHA)
Program Officer
Hasan, Ahmed AK
Project Start
1992-07-01
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
11
Fiscal Year
2003
Total Cost
$370,400
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mackman, Nigel; Spronk, Henri M H; Stouffer, George A et al. (2018) Dual Anticoagulant and Antiplatelet Therapy for Coronary Artery Disease and Peripheral Artery Disease Patients. Arterioscler Thromb Vasc Biol 38:726-732
Mackman, Nigel (2016) The Clot Thickens in Atherosclerosis. Arterioscler Thromb Vasc Biol 36:425-6
Vieira-de-Abreu, Adriana; Campbell, Robert A; Weyrich, Andrew S et al. (2012) Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 34:5-30
Lee, R D; Barcel, D A; Williams, J C et al. (2012) Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity. Thromb Res 129:80-5
Rondina, M T; Schwertz, H; Harris, E S et al. (2011) The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost 9:748-58
Kraemer, Bjoern F; Campbell, Robert A; Schwertz, Hansjorg et al. (2011) Novel anti-bacterial activities of ýý-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog 7:e1002355
Ollivier, Veronique; Wang, Jianguo; Manly, David et al. (2010) Detection of endogenous tissue factor levels in plasma using the calibrated automated thrombogram assay. Thromb Res 125:90-6
Pawlinski, Rafal; Mackman, Nigel (2010) Cellular sources of tissue factor in endotoxemia and sepsis. Thromb Res 125 Suppl 1:S70-3
Wang, J-G; Manly, D; Kirchhofer, D et al. (2009) Levels of microparticle tissue factor activity correlate with coagulation activation in endotoxemic mice. J Thromb Haemost 7:1092-8
Mackman, Nigel (2009) On the trail of microparticles. Circ Res 104:925-7

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