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)(1). In the United States ~750,000 patients/year develop sepsis syndrome(2). Cardiovascular dysfunction is a major complication associated with MODS morbidity and mortality. However, the mechanisms by which cardiovascular dysfunction occurs during sepsis/septic shock remain unclear. Endothelial cell dysfunction contributes to sepsis-induced MODS and high mortality. Endothelial cells express pattern recognition receptors (PRRs). PRRs recognize pathogen associated molecular patterns (PAMPs), initiate innate immune and inflammatory responses, and upregulate adhesion molecule expression, thus promoting immune cell infiltration and organ injury. Therefore, preservation of endothelial cell function is an important approach for attenuating sepsis-inducedmorbidity and mortality. During the last grant period, we discovered a novel role for endothelial specific HSPA12B in the regulation of endothelial cell function and innate immune response during CLP sepsis. HSPA12B is a newly discovered member of the HSP70 family. It is predominantly expressed in endothelial cells, and plays an important role in the induction of angiogenesis. We found that endothelial cell specific deficiency of HSPA12B (HSPA12B-/-) exacerbates mortality and worsens cardiac function in sepsis. In contrast, transgenic mice that over express endothelial HSPA12B exhibit significantly improved survival outcome and cardiac function in endotoxemia. Our findings raise an important question, i.e. how does endothelial HSPA12B have such a profound effect on the mortality and cardiovascular dysfunction associated with polymicrobial sepsis? We have made a novel observation that HSPA12B can translocate into the nucleus in endothelial cells. We also discovered that HSPA12B can be released from endothelial cells and transmitted into macrophages via exosomes where it downregulates inflammatory cytokine production. Our findings suggest that endothelial HSPA12B has an important role not only for endothelial cell function but also for inflammatory responses by immune cells during sepsis. Thus, endothelial HSPA12B could be an important effector that mediates crosstalk between endothelial cells and immune cells during sepsis. Based on the preliminary data, we hypothesize that ? endothelial HSPA12B is a novel endogenous effector which protects against sepsis induced cardiomyopathy by differentially regulating endothelial cell function and innate immune inflammatory responses?. To test these hypotheses, we propose three specific aims.
Specific aim 1. Investigate whether HSPA12B induced protection against septic cardiomyopathy is mediated via regulation of endothelial function.
Specific aim 2. Determine whether the protection against septic cardiomyopathy by endothelial HSPA12B is mediated by regulation of inflammatory cell responses.
Specific aim 3. Evaluate the therapeutic effect of HSPA12B in sepsis induced cardiomyopathy. The long term goals of this research 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.
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. In these patients, the overall mortality rate is 28.6% (~215,000 deaths/year). Those patients that survive the initial event, which may include trauma, may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due immune dysfunction and infection. It is well known that cardiovascular dysfunction is also associated with MODS morbidity and mortality. Attempts at developing effective therapies for sepsis/septic shock and MODS has proven to be exceedingly difficult. This is due, in part, to our incomplete understanding of the cellular and molecular mechanisms that mediate cardiac dysfunction in sepsis. Thus, it is clear that a better understanding of the molecular mechanisms leading to cardiac dysfunction during sepsis/septic shock is essential in developing adjunctive therapies that could decrease both morbidity and mortality. These studies will provide a mechanistic understanding of the cellular signaling pathways that are critical for cardiovascular function and/or dysfunction in sepsis. It may also be possible to apply this knowledge in a practical fashion to identify new and novel therapeutic approaches to prevent or manage cardiac dysfunction in sepsis/septic shock.
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