Innate Immunity and Cardiovascular Function in Sepsis

描述（由申请人提供）：危重患者经常出现复杂的疾病谱系，可能包括急性呼吸窘迫综合征（ARDS），全身炎症反应综合征（SIRS），败血症综合征和/或感染性休克和多器官功能障碍综合征（MODS）。在美国，每年约有75万患者出现脓毒症综合征。心血管功能障碍是与败血症发病率和死亡率相关的主要并发症。这种临床状况被称为“脓毒性心肌病”。脓毒性心肌病发生的机制尚不清楚。我们和其他人已经证明，toll样受体（TLR）介导的NF-κB通路的激活在脓毒症心肌病中起有害作用，而磷酸肌醇-3激酶(PI3K)/Akt信号的激活可以防止脓毒症心功能障碍。然而，在脓毒症中，细胞信号调节决定心功能命运的机制尚不清楚。在上一期资助期内，我们发现从脓毒症小鼠中分离的微颗粒明显抑制正常小鼠的心功能，并诱导巨噬细胞损伤。脓毒性微粒对心功能的影响与我们在脓毒性心脏病小鼠模型中观察到的心功能障碍相似。因此，脓毒症反应释放的微颗粒可能是脓毒症心肌病的重要病理机制。我们的研究结果提出了一个新的和新颖的概念，即败血症期间产生的微粒有助于心功能障碍。与之形成鲜明对比的是，PI3K/Akt信号被激活的细胞分泌的微粒可减轻脓毒症心肌病，抑制炎症反应，并可能有助于改善脓毒症的预后。基于这些数据，我们假设“在TLR/NF-κB和PI3K/Akt的调节下产生的微粒对败血症的心功能、全身炎症反应和生存结果有差异调节”。为了验证这一假设，我们提出了三个具体目标。特异性目的1将阐明多微生物脓毒症期间产生的微颗粒诱导脓毒性心肌病的机制。特异性目的2将定义脓毒性心肌病中PI3K/Akt信号激活时释放的微粒的保护机制。特异性目的3将研究10MER3的治疗效果，10MER3是一种合成的小分子，它刺激微颗粒的释放，减轻脓毒症心肌病，抑制炎症表型，提高脓毒症患者的生存结果。这项竞争性更新应用的长期目标是阐明脓毒症心肌病的细胞和分子机制，并开发新的治疗方法来改善脓毒症引起的心功能障碍相关的发病率和死亡率。

DESCRIPTION (provided by applicant): 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-κB 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-κB 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.