Central cholinergic regulation of inflammation

描述(申请人提供)：主要目的：提供对内毒素血症和多菌败血症时脑胆碱能通路在全身炎症反应的中枢胆碱能调节中的作用的机械性见解。背景：脓毒症和其他炎症性疾病的病理生理机制是由先天免疫反应失调和细胞因子水平异常升高所介导的，这些都是重要的实验治疗靶点。脓毒症和脓毒症后的发病率也可能与脑胆碱能系统的异常有关。我们最近的发现表明，在致死性炎症中，脑内胆碱能激活在降低全身促炎症细胞因子肿瘤坏死因子(TNF)和高迁移率族蛋白1(HMGB1)水平以及提高存活率方面发挥着关键作用。我们已经证明，M1受体激动剂在内毒素血症时抑制细胞因子反应并提高存活率，这种抗炎功能是通过脑M受体介导的。我们最近还表明，加兰他明，一种中枢作用的乙酰胆碱酯酶(AChE)抑制剂，通过脑M受体依赖信号抑制全身肿瘤坏死因子水平，并改善内毒素血症的存活率。我们已经证明加兰他明的抗炎作用是通过迷走神经传出的胆碱能抗炎途径来实现的。这条途径是大脑到免疫通讯的主要回路。胆碱能抗炎通路的激活也抑制了HMGB1水平，改善了实验性脓毒症的存活率。胆碱能抗炎通路介导了加兰他明的脑依赖抗炎作用。这些发现揭示了大脑胆碱能信号在炎症调节中的重要贡献。我们假设大脑中胆碱能M受体介导的激活水平与全身炎症反应之间存在相关性。这一假说将通过以下两个目标来检验：(SA#1)描述脑通路在内毒素血症时胆碱能调节炎症反应中的作用。我们将选择性地损伤大鼠两条主要的脑胆碱能通路--基底前脑胆碱能系统(BFCS)和桥脑中脑胆碱能系统(MCS)的神经元。然后，动物将被加兰他明治疗和内毒素血症，以评估选择性脑胆碱能功能障碍对肿瘤坏死因子、其他细胞因子和器官损伤的影响，以及加兰他明抗炎效果的幅度。(SA#2)评估盲肠结扎和穿孔(CLP)诱导的多菌败血症期间脑胆碱能对炎症反应的调节。我们将对大鼠脑内胆碱能BFCS和MCS神经元进行损伤，并将动物置于CLP中，以评估特定胆碱能去神经对HMGB1、其他细胞因子水平、器官损伤和多菌败血症模型存活的影响。加兰他明对全身细胞因子反应和存活的影响及其对特定脑功能障碍的依赖性将在治疗环境中进行评估。

DESCRIPTION (provided by applicant): The main objective: To provide mechanistic insight into the role of brain cholinergic pathways in the central cholinergic regulation of the systemic inflammatory response during endotoxemia and polymicrobial sepsis. Background: The pathophysiology of sepsis and other inflammatory disorders is critically mediated by dysregulated innate immune responses and abnormally elevated cytokine levels, which are important experimental therapeutic targets. Sepsis and post-sepsis morbidity may also be associated with abnormalities in the brain cholinergic system. Our recent findings demonstrate the critical role of cholinergic activation in the brain in reducing systemic levels of the pro-inflammatory cytokines tumor necrosis factor (TNF) and high mobility group box1 (HMGB1) and improving survival during lethal inflammation. We have demonstrated that M1 receptor agonists suppress cytokine responses and improve survival during endotoxemia and this anti- inflammatory function is mediated through brain muscarinic receptors. We have also recently shown that galantamine, a centrally-acting acetylcholinesterase (AChE) inhibitor suppresses systemic TNF levels and improves survival in endotoxemia through brain muscarinic receptor-dependent signaling. We have shown that the anti-inflammatory effect of galantamine is mediated through the efferent vagus nerve-based cholinergic anti-inflammatory pathway. This pathway is a major brain-to immune communication circuit. Activation of the cholinergic anti-inflammatory pathway, which mediates the brain-dependent anti-inflammatory effect of galantamine, also suppresses HMGB1 levels and improves survival in experimental sepsis. These findings reveal an important contribution of brain cholinergic signaling to the modulation of inflammation. We hypothesize that there is a correlation between the levels of cholinergic muscarinic receptor-mediated activation in the brain and the systemic inflammatory response. This hypothesis will be tested by the following 2 aims: (SA#1) Delineate the role of brain pathways in the cholinergic regulation of the inflammatory response during endotoxemia. We will perform selective lesions of neurons of two major brain cholinergic pathways the basal forebrain cholinergic system (BFCS), and the mesopontine cholinergic system (MCS) in rats. Then, animals will be treated with galantamine and subjected to endotoxemia to evaluate the effects of selective brain cholinergic dysfunction on TNF, other cytokines, and organ injury and the magnitude of galantamine anti-inflammatory efficacy. (SA#2) Evaluate the brain cholinergic regulation of the inflammatory response during cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We will perform lesions of brain cholinergic BFCS and MCS neurons in rats and will subject animals to CLP to evaluate the impact of specific cholinergic denervations on the levels of HMGB1, other cytokines, organ injury and survival in this model of polymicrobial sepsis. The effect of galantamine on the systemic cytokine response and survival and its dependence on specific brain dysfunction will be evaluated in therapeutic settings.