Regulation of Innate Immunity by the Sympathetic Nervous System Druing Sepsis

脓毒症期间交感神经系统对先天免疫的调节

• 批准号: 8519525
• 负责人: Eric J. Seeley
• 金额: $ 13.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519525
• 关键词: Ablation; Adrenal Medulla; Adrenergic Receptor; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Attenuated; Autonomic nervous system; Bacteria; Bacterial Infections; Binding; Biology; Blood; Blood Pressure; Bone Marrow; Bone Marrow Transplantation; CCL2 gene; Cardiomyopathies; Catecholamines; Cell Count; Cell Culture Techniques; Cells; Cessation of life; Chimera organism; Chronic; Clinical; Critical Illness; Cytokine Inducible SH2-Containing Protein; Goals; Hormones; Hospital Costs; Host Defense; IV Fluid; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Inflammatory; Inflammatory Response; Injury; Innovative Therapy; Interleukin-6; Klebsiella pneumonia bacterium; Knowledge; Lead; Light; Measurable; Measures; Modeling; Molecular; Mus; Natural Immunity; Nerve; Nerve Endings; Norepinephrine; Organ; Organ failure; Pathway interactions; Patients; Peritoneal; Peritoneal Macrophages; Peritonitis; Physiological; Predisposition; Property; Proteins; Psychological Stress; Public Health; Rattus; Receptor Signaling; Regulation; Research; Research Proposals; Rodent Model; Role; Sepsis; Sepsis Syndrome; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Stream; Stress; Sympathectomy; Sympathetic Nervous System; TLR4 gene; Testing; Therapeutic; Tissues; Transgenic Mice; Translating; United States; base; cholinergic; cytokine; fighting; hemodynamics; immunoregulation; improved; in vitro testing; in vivo; macrophage; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutics; receptor; research study; response; septic

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.

描述（由申请人提供）：当细菌逃避宿主防御进入血液时，就会出现脓毒症的临床症状。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原因是感染期间器官衰竭和死亡。在美国，败血症每年折磨着70多万人，导致20多万人死亡。目前对败血症的治疗包括早期抗生素和强力静脉输液。然而，旨在平息导致器官损伤的免疫反应的治疗尚未取得成功。为了提高这种常见和毁灭性疾病的死亡率，需要基于新的生物学发现的新的治疗策略。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。本研究计划的目的是研究败血症期间神经如何调节免疫系统。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在感染期间改变生存。初步研究表明，减少去甲肾上腺素（一种交感神经在应激状态下释放的化合物）的释放，可以提高感染小鼠模型的存活率。这3项研究的目的是系统地研究去甲肾上腺素和巨噬细胞等先天免疫细胞在感染过程中如何相互作用。具体来说，目的1将研究去甲肾上腺素如何改变小鼠和大鼠的血流动力学。目的2将鉴定巨噬细胞上帮助应激激素向免疫细胞发出信号的细胞受体。最后，目的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的反应（细菌负荷、细胞计数、炎症细胞因子）的测量。此外，在细胞培养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新的生物学机制，可能转化为败血症的新疗法。这些研究也可能说明外源性去甲肾上腺素（通常用于提高危重病人的血压）的全身管理是如何改变免疫力的。最后，这些研究可能阐明慢性生理或心理应激如何改变对感染的易感性。