Central cholinergic regulation of inflammation

描述（由申请人提供）：主要目的：在内毒素血症和多微生物败血症期间，为脑胆碱能通路在中枢胆碱能调节全身性炎症反应中的作用提供机制见解。背景：脓毒症和其他炎性疾病的病理生理是由先天免疫反应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，脑胆碱能激活在降低促炎细胞因子肿瘤坏死因子（TNF）和高迁移率组1 （HMGB1）的全身水平和提高致死性炎症期间的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反应，提高内毒素血症期间的存活率，这种抗炎功能是通过脑毒蕈碱受体介导的。我们最近也表明，加兰他敏，一种中枢作用的乙酰胆碱酯酶（AChE）抑制剂，通过脑毒蕈碱受体依赖的信号传导抑制全身TNF水平，提高内毒素血症患者的生存率。我们已经证明，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途径介导的。这是一条主要的脑-免疫通讯线路。激活介导加兰他敏脑依赖性抗炎作用的胆碱能抗炎通路，也可抑制HMGB1水平，提高实验性败血症的生存率。这些发现揭示了脑胆碱能信号对炎症调节的重要贡献。我们假设大脑中胆碱能毒蕈碱受体介导的激活水平与全身炎症反应之间存在相关性。这一假设将通过以下两个目标进行验证：（SA#1）描述内毒素血症期间脑通路在胆碱能调节炎症反应中的作用。我们将对大鼠两种主要脑胆碱能通路——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，用加兰他敏治疗动物并进行内毒素血症，以评估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程度。评估盲肠结扎和穿刺（CLP）诱导的多微生物脓毒症中炎症反应的脑胆碱能调节。我们将对大鼠脑胆碱能BFCS和MCS神经元进行损伤，并对动物进行CLP，以评估特异性胆碱能去神经化对多微生物脓毒症模型中HMGB1水平、其他细胞因子、器官损伤和存活的影响。加兰他敏对全身细胞因子反应和生存的影响及其对特定脑功能障碍的依赖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. PUBLIC HEALTH RELEVANCE: The proposed study will examine the role of the brain cholinergic system in controlling the release of cytokines that mediate lethal inflammation. The results generated from this study will advance our understanding of the regulation of pathological mechanisms in sepsis and other devastating inflammatory diseases, which in turn may provide a rationale/platform for the design of novel and efficient treatments.