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.
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