Central cholinergic regulation of inflammation

炎症的中枢胆碱能调节

• 批准号: 8042116
• 负责人: Kevin J Tracey
• 金额: $ 28.22万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042116
• 关键词: Acetylcholinesterase Inhibitors; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Brain; Cholinergic Agents; Communication; Denervation; Dependence; Development; Disease; Endotoxemia; Functional disorder; Galantamine; Hippocampus (Brain); Hypothalamic structure; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Learning; Lesion; Ligation; Light; Mediating; Memory; Modeling; Morbidity - disease rate; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Neurons; Organ; Pathway interactions; Peripheral; Physiological; Physiology; Prosencephalon; Puncture procedure; Rattus; Regulation; Research; Rodent Model; Role; Sepsis; Signal Transduction; Sleep; Structure; System; Techniques; Testing; Thalamic structure; Therapeutic; Tumor Necrosis Factor-alpha; Vagus nerve structure; basal forebrain; base; brain pathway; cholinergic; controlled release; cytokine; design; improved; innovation; insight; neurophysiology; novel; response; therapeutic target

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.

描述（由申请人提供）：主要目的：提供机械洞察脑胆碱能途径在内蛋白毒素和多数毒性败血症期间全身性炎症反应中心胆碱能调节中的作用。背景：败血症和其他炎症性疾病的病理生理学是由异常的先天免疫反应和异常升高的细胞因子水平介导的，这是重要的实验治疗靶标。败血症和盐后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，胆碱能激活在大脑中的关键作用在降低促炎性细胞因子肿瘤坏死因子（TNF）和高迁移率组BOX1（HMGB1）的全身水平中，并改善致命性炎症期间的存活率。我们已经证明，M1受体激动剂抑制细胞因子反应并改善内毒素血症期间的存活，这种抗炎症功能是通过脑毒蕈碱受体介导的。我们最近还表明，甘兰胺是一种中心作用的乙酰胆碱酯酶（ACHE）抑制剂可抑制全身性TNF水平，并通过脑毒蕈碱受体依赖性信号传导提高内毒素血症的存活率。我们已经表明，甘氨酸的抗炎作用是通过传出迷走神经基胆碱能抗炎途径介导的。该途径是一种主要的大脑对免疫通信电路。胆碱能抗炎途径的激活介导了甘氨酸的脑依赖性抗炎作用，也抑制了HMGB1水平并改善了实验性败血症的生存。这些发现揭示了大脑胆碱能信号传导对炎症调节的重要贡献。我们假设胆碱能受体介导的大脑激活与全身性炎症反应之间存在相关性。该假设将通过以下两个目的进行检验：（SA＃1）描述脑途径在内毒素血症期间炎症反应的胆碱能调节中的作用。我们将对两种主要脑胆碱能途径的神经元进行选择性病变。基底前胆碱能系统（BFCS）和大鼠中桥桥胆碱能系统（MCS）。然后，将用甘氨酸治疗动物，并患有内毒素血症，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甘氨酸抗炎功效的大小。 （SA＃2）评估盲肠结扎和穿刺（CLP）诱导的多菌血性败血症期间炎症反应的脑胆碱能调节。我们将对大鼠的脑胆碱能BFC和MCS神经元进行病变，并将使动物患动物，以评估特定的胆碱能否对HMGB1水平，其他细胞因子，器官损伤，器官损伤和生存中的影响。甘氨酸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性将在治疗环境中进行评估。 公共卫生相关性：拟议的研究将研究脑胆碱能系统在控制介导致命炎症的细胞因子释放中的作用。这项研究产生的结果将促进我们对败血症和其他破坏性炎症性疾病中病理机制的调节的理解，这反过来又可能为设计新颖有效治疗的设计提供了理由/平台。