Regulation of Innate Immunity by the Sympathetic Nervous System Druing Sepsis

描述（由申请人提供）：当细菌逃避宿主防御并进入血流时，败血症的临床综合征发生。虽然细菌可以直接损害宿主组织，但对细菌的过度炎症反应更常见的是感染期间器官衰竭和死亡的原因。败血症在美国每年折磨超过70万人，并导致超过20万人死亡。目前脓毒症的治疗包括早期抗生素和积极的静脉输液。然而，旨在平息导致器官损伤的免疫反应的治疗并不成功。需要基于新的生物学发现的新的治疗策略，以提高这种常见和毁灭性疾病的死亡率。 越来越多的证据表明，神经向免疫细胞发送信号，这些信号调节免疫细胞对各种刺激的反应。这项研究计划的目标是研究神经如何在脓毒症期间调节免疫系统。具体来说，这项研究计划旨在确定导致“战斗或逃跑”反应的交感神经系统如何改变感染期间的生存率。研究表明，减少去甲肾上腺素（一种在压力下从交感神经释放的化合物）的释放，可以提高感染小鼠模型的存活率。这三项研究的目标是系统地研究去甲肾上腺素和先天免疫细胞（如巨噬细胞）在感染过程中如何相互作用。具体来说，目标1将研究去甲肾上腺素消融如何改变小鼠和大鼠的血流动力学。目标2将确定巨噬细胞上的细胞受体，帮助应激激素向免疫细胞发出信号。最后，目标3的目标是确定检测应激激素的信号通路如何与检测细菌的信号通路相互作用。为了研究这些目标，将进行生存研究和宿主对感染反应的测量（细菌负荷、细胞计数、炎症细胞因子）。此外，在细胞培养物中生长的巨噬细胞将用于研究去甲肾上腺素影响巨噬细胞功能的受体和分子。最后，所有这些细胞培养结果的相关性将在使用骨髓移植和转基因小鼠的小鼠感染模型中进行测试。 拟议研究的长期目标是确定可能转化为脓毒症新疗法的新生物学机制。这些研究也可以说明如何全身施用外源性去甲肾上腺素，这是通常用于增加危重患者的血压，改变免疫力。最后，这些研究可能揭示慢性生理或心理压力如何改变感染的易感性。

DESCRIPTION (provided by applicant): When bacteria evade host defenses and enter the blood stream, the clinical syndrome of sepsis ensues. Although bacteria can directly damage host tissues, an over exuberant inflammatory response to bacteria is more commonly the cause of organ failure and death during infection. Sepsis afflicts over 700,000 people yearly in the United States and leads to more than 200,000 deaths. Current treatments for sepsis include early antibiotics and aggressive intravenous fluids. However, treatments aimed at calming the immune response that leads to organ damage have not been successful. New therapeutic strategies based on novel biologic discoveries are needed in order to improve mortality from this common and devastating illness. Mounting evidence indicates that nerves send signals to immune cells and that these signals regulate how immune cells respond to various stimuli. The goal of this research proposal is to investigate how nerves regulate the immune system during sepsis. Specifically, this research proposal aims to identify how the sympathetic nervous system, which leads to the "fight or flight" response, alters survival during infection. Preliminar studies indicate that decreasing the release of norepinephrine, a compound released from sympathetic nerves during stress, improves survival in mouse models of infection. The goal of the 3 research aims is to systematically investigate how norepinephrine and innate immune cells, like macrophages, interact during infection. Specifically, aim 1 will investigate how ablatin of norepinephrine alters hemodynamics in mice and rats. Aim 2 will identify the cellular receptors on macrophages that help stress hormones signal to immune cells. Lastly, the goal of aim 3 is to determine how the signaling pathways that detect stress hormones interact with the signaling pathways that detect bacteria. Survival studies and measures of host response to infection (bacterial loads, cell counts, inflammatory cytokines), will be performed in order to investigate these aims. In addition, macrophages grown in cell culture will be used to study the receptors and molecules through which norepinephrine influences macrophages function. Finally, the relevance of all of these cell culture findings will be tested in mouse models of infection using bone marrow transplants and transgenic mice. The long-term goal of the proposed research is to identify new biologic mechanisms that might translate into novel therapies for sepsis. These studies may also illustrate how the systemic administration of exogenous norepinephrine, which is commonly used to increase blood pressure in critically ill patients, alters immunity. Lastly, these studies may shed light on how chronic physiologic or psychologic stress alter susceptibility to infection.