Macrophage Inactivation in Sepsis after Shock or Trauma

休克或创伤后脓毒症中巨噬细胞失活

基本信息

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
项目类别：
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

项目摘要

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，这项资助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，其原理连接大脑与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。炎症反射。自然。 2002 年 12 月 19-26 日；420:853-9)。脓毒症、内毒素血症动物模型的临床前研究缺血再灌注、创伤和休克表明，该途径可用于开发新的治疗患有这些疾病和其他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，但仍然存在有关细胞、分子和神经机制的重要未解答问题。在具体目标 1 中，我们将检验胆碱能抗炎途径抑制细胞因子机制的假设需要胆碱能神经输入脾脏中产生细胞因子的细胞。在具体目标 2 中，我们将测试假设大脑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）专门剖析大脑免疫调节的功能途径反应是独特的、新颖的，并且可能提供有关神经系统的重要新信息免疫反应的控制。引领该领域发展的Tracey实验室现已特别适合做这些研究。