Cholinergic anti-inflammatory mechanisms in sepsis and septic shock

脓毒症和脓毒性休克中的胆碱能抗炎机制

基本信息

批准号：
8770116
负责人：
DONALD B HOOVER
金额：
$ 33.73万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770116
关键词：
Acetylcholine Acute Address Adult Respiratory Distress Syndrome Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Attenuated Autonomic nervous system Biochemical Blood Cardiac Celiac ganglion Cells Cessation of life Cholinergic Fibers Clinical Complex Critical Illness Cytokine Suppression Data Disease Dose Efferent Neurons Foundations Functional disorder GTS-21 Immune Immune response Immune system Immunosuppression In Situ Infection Inflammation Inflammatory Inflammatory Response Knowledge Life Link Malpighian corpuscles Mediating Mediator of activation protein Methods Modeling Multiple Organ Failure Mus Nerve Nerve Fibers Neurons Nicotinic Receptors Norepinephrine Organ failure Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Population Pre-Clinical Model Production Pulmonary Pathology Reflex action Regimen Research Role Sepsis Sepsis Syndrome Septic Shock Signal Transduction Site Source Spleen Splenocyte Staging Synapses T-Lymphocyte Therapeutic Treatment Protocols Up-Regulation Work autocrine cardiac depression catalyst cellular longevity cholinergic clinically relevant clinically significant cytokine design effective therapy improved macrophage monocyte neuroregulation noradrenergic novel paracrine preclinical study prevent protein expression public health relevance receptor relating to nervous system response septic treatment duration

项目摘要

DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, septic shock and multiple organ dysfunction syndrome (MODS). Attempts at developing effective therapies for sepsis/septic shock and MODS have proven to be exceedingly difficult. We hypothesize that the systemic inflammatory response to sepsis can be attenuated or aborted by using an alpha7 nicotinic receptor agonist to activate the cholinergic anti- inflammatory pathway. This pathway is part of a reflex arc that modulates immune responses by acting at the spleen to suppress production of pro-inflammatory cytokines by macrophages. The neural components of this pathway comprise preganglionic vagal efferent nerves (cholinergic) and their target postganglionic sympathetic neurons (noradrenergic) that innervate the spleen. Recent evidence suggests that local release of norepinephrine activates a cholinergic phenotype in splenic T cells, but in situ expression of cholinergic markers in the spleen has not been explored. Suppression of cytokine production by macrophages is mediated by alpha7 nicotinic receptors. Activated T cells may be the source of acetylcholine (ACh) that stimulates these receptors. However, macrophages can also acquire a cholinergic phenotype and might be an additional source for ACh. Furthermore, splenic monocytes also produce inflammatory cytokines and could be additional targets for ACh. Thus, there are many unknowns regarding mechanisms involved in converting the neural signal into an anti-inflammatory/anti-sepsis response. The clinical significance of the cholinergic anti-inflammatory pathway is amplified by evidence that its benefits appear to reach beyond the spleen, but the full extent of the systemic response is yet to be established. This project will address these gaps in knowledge by using a clinically relevant murine model of polymicrobial sepsis (CLP) and evaluating histochemical, biochemical, and therapeutic responses evoked by treatment with a drug (GTS-21) that activates the cholinergic anti-inflammatory pathway by stimulation of alpha7 nicotinic receptors. Aim 1 will employ biochemical and immunohistochemical methods to: 1) identify and characterize splenocytes that make and/or respond to ACh and 2) evaluate effects of GTS-21 to increase ACh concentration in the spleen and suppress production of inflammatory cytokines by splenocytes. Aim 2 will evaluate the therapeutic response of septic mice to treatment with GTS-21. Different dosing regimens will be used to evaluate the efficacy of GTS-21 at preventing, attenuating, or reversing sepsis-induced cardiac dysfunction, pulmonary pathology, and immunosuppression. Results from this study will expand our understanding of the mechanisms and therapeutic potential of the cholinergic anti-inflammatory pathway.

描述（由申请人提供）：重症患者经常会发展出复杂的疾病谱，其中可能包括急性呼吸窘迫综合征，全身性炎症反应综合征，化粪池休克和多器官功能障碍综合征（MODS）。事实证明，尝试开发有效的败血症/败血性休克和mod的疗法的尝试非常困难。我们假设通过使用α7烟碱受体激动剂激活胆碱能抗炎性途径，可以减弱或流产对败血症的全身性炎症反应。该途径是反射弧的一部分，该反射弧是通过在脾脏作用以抑制巨噬细胞抑制促炎性细胞因子的产生来调节免疫反应的一部分。该途径的神经成分包括神经前神经传出神经（胆碱能）及其靶向靶后交感神经元（去甲肾上腺素能），从而支配脾脏。最近的证据表明，去甲肾上腺素的局部释放激活脾T细胞中的胆碱能表型，但尚未探索脾脏中胆碱能标记物的原位表达。巨噬细胞抑制细胞因子的产生是由α7烟碱受体介导的。活化的T细胞可能是刺激这些受体的乙酰胆碱（ACH）的来源。但是，巨噬细胞也可以获得胆碱能表型，并且可能是ACH的附加来源。此外，脾单核细胞还会产生炎症细胞因子，并且可能是ACH的其他靶标。因此，关于将神经信号转化为抗炎/抗盐反应的机制有许多未知数。胆碱能抗炎途径的临床意义通过证据表明其益处似乎超出了脾脏，但全身反应的全部范围尚未确定。该项目将通过使用临床相关的多肌醇败血症（CLP）的临床相关鼠模型来解决这些差距，并评估通过药物（GTS-21）治疗引起的组织化学，生化和治疗反应（GTS-21），从而激活胆碱能抗炎性途径，通过刺激氧气受体受到促氧化抗炎途径。 AIM 1将采用生化和免疫组织化学方法来：1）确定和表征对ACH进行和/或反应的脾细胞，以及2）评估GTS-21的作用，以增加脾脏的ACH浓度并抑制脾细胞的炎症细胞因子的产生。 AIM 2将评估化粪池小鼠对用GTS-21治疗的治疗反应。不同的给药方案将用于评估GTS-21在预防，衰减或逆转败血症引起的心脏功能障碍，肺病理学和免疫抑制的功效。这项研究的结果将扩大我们对胆碱能抗炎途径的机制和治疗潜力的理解。