This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction This application focuses on the novel role of extracellular histones in the pathophysiology of sepsis, particularly aiming to validate the histones as a biomarker, mediator and therapeutic target for severe sepsis and accompanying multiple organ dysfunction or failure (MODS/MOF). Severe sepsis is a major medical problem responsible for approximately 750,000 ICU admissions at a cost of over 17 billion dollars and 225,000 deaths in the U.S. annually. Our group has recently discovered that nuclear histones are released in the extracellular environment in response to inflammatory challenges and are important mediators of sepsis-induced organ failure and death. Histone plasma levels correlate with organ dysfunction and death in animals (mice and baboons), as well as in humans with sepsis. Xigris (activated protein C) cleaves histones and reduces their toxicity. Histone inhibition with antibodies or blocking peptides rescue mice from experimental lethal sepsis. The objectives of this proposal are: (i) to validate extracellular histones as important biomarkers that mediate of tissue damage, ultimately leading to organ failure, and (ii) characterize the therapeutic potential of two histone blocking strategies.
Aim 1 employs exogenous histone challenge to characterize the in vivo cytotoxic, inflammatory and microthrombotic effects of histones and therapeutic targeting of histones in four mouse models of sepsis.
Aim 2 will translate the histone inhibition approaches to a clinically relevant model of E. coli sepsis in a large animal.
Aim 3. Will validate the plasma histones as a prognostic biomarker for organ dysfunction that correlates with clinical outcomes, and helps to identify the patients who will benefit from specific antisepsis therapies with histone blockade. Overall, this project will advance the understanding of the pathophysiology of sepsis induced organ damage, will validate new biomarkers and develop a novel potential treatment for patients with sepsis and MOF.
Sepsis is a multi-factorial disorder that triggers an uncontrolled inflammatory response, ultimately leading to multiple organ failure and death. We have evidence that during sepsis, histones are released in the extracellular environment and are mediators of organ dysfunction and lethality. The objectives of this proposal are to validate extracellular histones as an important cause and biomarker of tissue damage and to test two histone-blocking approaches as potential therapeutics in sepsis.
|Lupu, C; Herlea, O; Tang, H et al. (2013) Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia. J Thromb Haemost 11:142-8|
|Taylor Jr, Fletcher B; Kinasewitz, Gary T; Lupu, Florea (2012) Pathophysiology, staging and therapy of severe sepsis in baboon models. J Cell Mol Med 16:672-82|
|Gavins, Felicity N E; Russell, Janice; Senchenkova, Elena L et al. (2011) Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S. Blood 117:4125-33|
|Esmon, Charles T; Esmon, Naomi L (2011) The link between vascular features and thrombosis. Annu Rev Physiol 73:503-14|
|Xu, Jun; Zhang, Xiaomei; Monestier, Marc et al. (2011) Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 187:2626-31|
|Esmon, C T; Xu, J; Lupu, F (2011) Innate immunity and coagulation. J Thromb Haemost 9 Suppl 1:182-8|
|Silasi-Mansat, Robert; Zhu, Hua; Popescu, Narcis I et al. (2010) Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116:1002-10|