Innate Immunity and Cardiovascular Function in Sepsis

描述(申请人提供)：危重患者经常出现复杂的疾病谱，可能包括急性呼吸窘迫综合征(ARDS)、全身炎症反应综合征(SIRS)、脓毒症综合征和/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75万名患者患上败血症综合征。心血管功能障碍是导致脓毒症发病率和死亡率的主要并发症。这种临床症状被称为“败血症心肌病”。败血症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(Toll样受体)介导的NF-κB通路的激活在脓毒症心肌病中起着有害的作用，而磷脂酰肌醇-3激酶(PI3K)/AKT信号的激活对脓毒症时的心功能障碍具有保护作用。然而，细胞信号调节决定脓毒症患者心脏功能命运的机制仍不清楚。在最后一次资助期间，我们发现从脓毒症小鼠分离的微粒显著抑制正常小鼠的心功能，并诱导巨噬细胞损伤。败血症微粒对心脏功能的影响类似于我们在败血症心脏病小鼠模型中观察到的心脏功能障碍。因此，脓毒症时释放的微粒可能是败血症心肌病的重要病理机制。我们的发现提出了一个新的新概念，即在脓毒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，具有激活的PI3K/Akt信号的细胞分泌的微粒可以减轻败血症心肌病，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“在脓毒症中，TLR/NF-κB和PI3K/AKT调节产生的微粒对心功能、全身炎症反应和生存结局具有不同的调节作用”。为了检验这一假设，我们提出了三个具体目标。具体目标1将阐明在多菌败血症过程中产生的微粒引起败血症心肌病的机制。具体目标2将确定败血症心肌病中PI3K/Akt信号激活所释放的微粒的保护机制。具体目标3将研究10MER3的治疗效果。10MER3是一种人工合成的小分子，可以刺激微粒的释放，减轻败血症心肌病，抑制炎症表型，改善脓毒症的生存结局。这一竞争性更新应用的长期目标是阐明败血症心肌病的细胞和分子机制，并开发新的治疗方法来改善与脓毒症相关的心功能障碍的发病率和死亡率。

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.