The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock and multiple organ dysfunction syndrome (MODS). In the United States ~750,000 patients/year develop sepsis syndrome. Cardiovascular dysfunction is a major complication associated with the morbidity and mortality of sepsis. This clinical condition has been termed """"""""septic cardiomyopathy"""""""". The mechanisms by which septic cardiomyopathy occur remain unclear. We and others have demonstrated that activation of Toll-like receptor (TLR) mediated NF-?B pathway plays a deleterious role in septic cardiomyopathy, while activation of phosphoinositide-3 kinase (PI3K)/Akt signaling protects against cardiac dysfunction in sepsis. However, the mechanisms by which modulation of cellular signaling determines the fate of cardiac function in sepsis are still unclear. During the last grant period, we discovered that microparticles isolated from septic mice significantly suppress cardiac function in normal mice and induce injury of macrophages. The effect of septic microparticles on cardiac function is similar to the cardiac dysfunction we have observed in a murine model of septic cardiopathy. Thus, microparticles released in response to sepsis may be an important pathologic mechanism of septic cardiomyopathy. Our findings suggest a new and novel concept that microparticles generated during sepsis contribute to cardiac dysfunction. In striking contrast, microparticles secreted by cells with activated PI3K/Akt signaling attenuate septic cardiomyopathy, suppress inflammatory responses and may contribute to improved outcome in sepsis. Based on these data we hypothesize that """"""""microparticles generated in response to modulation of TLR/NF-?B and PI3K/Akt differentially regulate cardiac function, systemic inflammatory responses and survival outcome in sepsis"""""""". To test this hypothesis we propose three specific aims.
Specific Aim 1 will elucidate the mechanisms by which the microparticles generated during polymicrobial sepsis induce septic cardiomyopathy.
Specific aim 2 will define the protective mechanisms of microparticles released in response to activation of PI3K/Akt signaling in septic cardiomyopathy.
Specific aim 3 will investigate the therapeutic efficacy of 10MER3 a synthetic, small molecule which stimulates the release of microparticles that attenuate septic cardiomyopathy, inhibits the inflammatory phenotype and improves survival outcome in sepsis. The long term goals of this competitive renewal application are to elucidate the cellular and molecular mechanisms of septic cardiomyopathy and to develop new and novel therapies to ameliorate the morbidity and mortality associated with sepsis induced cardiac dysfunction.

Public Health Relevance

This research will examine the cellular and molecular mechanisms of heart failure in critically ill patients with infections. Based on the results of the last grant period we have evidence that small particles are released from cells in response to infectious disease. These particles carry nucleic acids and proteins which serve as a form of communication between cells. In this case, the particles released during sepsis communicate with heart cells and decrease their function. However, by modifying cellular activity it is possibl to elicit particles which do not suppress cardiac function in septic patients. This may provide us with an avenue of investigation into new drugs/treatments for the heart failure that is often associated with infections. The long term goals of this research are to better understand how heart failure occurs during infections and, of greater importance, how we might be able to prevent and/or treat the heart failure associated with some infectious diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Dunsmore, Sarah
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East Tennessee State University
Schools of Medicine
Johnson City
United States
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