Macrophage Inactivation in Sepsis after Shock or Trauma

休克或创伤后脓毒症中巨噬细胞失活

• 批准号: 7933295
• 负责人: Kevin J Tracey
• 金额: $ 27.81万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933295
• 关键词: Ablation; Address; Agonist; Anatomy; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Biological; Brain; Cells; Cholinergic Agonists; Colitis; Cytokine Suppression; Development; Disease; Electric Stimulation; Endotoxemia; Endotoxins; Functional disorder; Grant; HMGB1 gene; Heart Rate; Hemorrhagic Shock; Host Defense; Hour; Immune response; Immune system; Immunohistochemistry; In Situ; Infection; Inflammatory; Ischemia; Knowledge; Laboratories; Measurement; Mediating; Modeling; Molecular; Muscarinics; Nature; Nerve; Nervous system structure; Neurotransmitter Receptor; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Peripheral; Production; Recording of previous events; Reflex action; Reperfusion Therapy; Research; Research Design; Research Personnel; Reticuloendothelial System; Role; Sepsis; Shock; Signal Transduction; Spleen; Structure of splenic vein; Surgical Injuries; System; TNF gene; Testing; Therapeutic; Therapeutic Effect; Time; Trauma; Upper arm; Vagus nerve structure; base; brain pathway; cholinergic; cholinergic neuron; clinically relevant; cytokine; intraperitoneal; macrophage; mind control; neuromechanism; neurophysiology; neurotransmitter release; novel; pre-clinical; preclinical study; programs; receptor; relating to nervous system; research study; response; response to injury; therapy design; vagus nerve stimulation

The principal objective of this grant, since its inception in 1998, has been to elucidate biological mechanisms that regulate the immune response to injury and infection. This led to the discovery of a neurophysiological mechanism by which the brain controls the peripheral immune system through the vagus nerve, the principle cholinergic nerve that connects the brain to the organs of the reticuloendothelial system. This discovery opened a new field of research, now termed "The Inflammatory Reflex" (Tracey KJ. The inflammatory reflex. Nature. 2002 Dec 19-26;420:853-9). Preclinical studies in animals models of sepsis, endotoxemia, ischemia-reperfusion, trauma, and shock have revealed that this pathway may be exploited to develop new therapies to treat patients with these and other diseases caused by cytokine overproduction. While these studies have clearly demonstrated a major role for this pathway in controlling cytokine release, there remain important unanswered questions about cellular, molecular, and neural mechanisms. In Specific Aim 1 we will test the hypothesis that the mechanism of cytokine suppression by the cholinergic anti-inflammatory pathway requires cholinergic neural input to cytokine producing cells in spleen. In Specific Aim 2 we will test the hypothesis that activation of cholinergic mechanisms in brain regulates cytokine release during endotoxemia, and in a standardized preclinical therapeutic model of CLP sepsis. These studies are essential to move the field forward. The concept of applying a classical neurophysiological study design (based on either electrically stimulating the vagus nerve or administering a selective neurotransmitter receptor agonist to activate a brain network) to specifically dissect a functional pathway for brain modulation of the immune response is singular, novel, and likely to provide significant new information about the nervous system control of the immune response. The Tracey laboratory, which has led the development of this field, is now particularly well suited to do these studies.

自1998年设立以来，该基金的主要目标是阐明生物学机制 调节对损伤和感染的免疫反应。这导致了一种神经生理学的发现， 大脑通过迷走神经控制外周免疫系统的机制， 连接大脑和网状内皮系统器官的胆碱能神经。这一发现 开辟了一个新的研究领域，现在被称为“炎症反射”（Tracey KJ.炎症反应 自然2002年12月19-26日;420：853-9）。在败血症、内毒素血症、 缺血-再灌注、创伤和休克已经揭示了这一途径可能被用来开发新的 用于治疗患有这些和其它由细胞因子过度产生引起的疾病的患者的疗法。虽然这些 研究已经清楚地证明了该途径在控制细胞因子释放中的主要作用，但仍然存在 关于细胞、分子和神经机制的重要未解问题。具体目标1： 检验胆碱能抗炎通路抑制细胞因子的机制 需要胆碱能神经输入到脾中的细胞因子产生细胞。在具体目标2中，我们将测试 假设脑中胆碱能机制的激活调节内毒素血症期间细胞因子的释放， 以及CLP脓毒症的标准化临床前治疗模型。这些研究对于推动 场向前。应用经典神经生理学研究设计的概念（基于 电刺激迷走神经或施用选择性神经递质受体激动剂， 激活大脑网络）来特异性地剖析用于免疫调节的大脑功能通路。 反应是单一的，新颖的，并可能提供有关神经系统的重要新信息 控制免疫反应。领导这一领域发展的特雷西实验室， 特别适合做这些研究。