Macrophage Inactivation in Sepsis after Shock or Trauma

自1998年设立以来，这项资助的主要目的一直是阐明生物学机制。 来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，原理 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。炎症反射。 大自然。2002年12月19日至26日；420：853-9)。败血症、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，这一途径可能被利用来开发新的 治疗这些疾病和其他由细胞因子过度产生引起的疾病的疗法。而这些 研究已经清楚地表明，这一途径在控制细胞因子释放方面发挥了重要作用 关于细胞、分子和神经机制的重要未解问题。在具体目标1中，我们将 胆碱能抗炎途径抑制细胞因子机制的假设检验 需要胆碱能神经输入到脾中产生细胞因子的细胞。在特定的目标2中，我们将测试 假设脑内胆碱能机制的激活调节内毒素血症时细胞因子的释放， 和标准化的CLP脓毒症临床前治疗模型。这些研究对于推动 前场前锋。应用经典神经生理学研究设计的概念(基于 电刺激迷走神经或使用选择性神经递质受体激动剂 激活大脑网络)来专门剖析大脑调节免疫的功能路径 反应是独特的，新颖的，可能会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现在 特别适合做这些研究。

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.