Central cholinergic regulation of inflammation

描述（由申请方提供）：主要目的：提供内毒素血症和多微生物脓毒症期间脑胆碱能通路在全身炎症反应中枢胆碱能调节中的作用的机制见解。背景资料：脓毒症和其他炎性疾病的病理生理学是由先天免疫应答失调和细胞因子水平异常升高介导的，这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。我们最近的研究结果表明，在致命的炎症过程中，脑中胆碱能激活在降低促炎细胞因子肿瘤坏死因子（TNF）和高迁移率族蛋白1（HMGB1）的全身水平和提高生存率方面发挥着关键作用。我们已经证明，M1受体激动剂抑制细胞因子的反应，并提高生存期内毒素血症，这种抗炎功能是通过脑毒蕈碱受体介导的。我们最近还表明，加兰他敏，中枢作用乙酰胆碱酯酶（AChE）抑制剂抑制全身TNF水平，并通过脑毒蕈碱受体依赖性信号传导改善内毒素血症的生存。我们已经表明，加兰他敏的抗炎作用是通过传出迷走神经为基础的胆碱能抗炎通路介导的。这条通路是一个主要的大脑免疫通讯回路。胆碱能抗炎通路的激活介导加兰他敏的脑依赖性抗炎作用，也抑制HMGB1水平并改善实验性脓毒症的存活率。这些发现揭示了脑胆碱能信号对炎症调节的重要贡献。我们推测，胆碱能毒蕈碱受体介导的激活水平在大脑和全身炎症反应之间存在相关性。该假设将通过以下2个目的进行检验：（SA#1）描述脑通路在内毒素血症期间炎症反应的胆碱能调节中的作用。我们将对大鼠的两个主要脑胆碱能通路基底前脑胆碱能系统（BFCS）和中桥脑胆碱能系统（MCS）的神经元进行选择性损伤。然后，将用加兰他敏处理动物并使其经受内毒素血症，以评价选择性脑胆碱能功能障碍对TNF、其他细胞因子和器官损伤的影响以及加兰他敏抗炎功效的大小。(SA#2）评价盲肠结扎和穿孔（CLP）诱导的多微生物脓毒症期间炎症反应的脑胆碱能调节。我们将在大鼠中进行脑胆碱能BFCS和MCS神经元的损伤，并将动物进行CLP，以评估特定胆碱能去神经对该多微生物脓毒症模型中HMGB1、其他细胞因子、器官损伤和存活率水平的影响。将在治疗环境中评价加兰他敏对全身细胞因子反应和存活率的影响及其对特定脑功能障碍的依赖性。

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.