Cytokines and Sympathetic Activation in Heart Failure

心力衰竭中的细胞因子和交感神经激活

基本信息

批准号：
8758110
负责人：
Robert B Felder
金额：
$ 37.75万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8758110
关键词：
Adverse effects Angiotensin II Arteries Attention Attenuated Automobile Driving Blood Blood - brain barrier anatomy Brain Cardiovascular Diseases Cardiovascular system Clinical Clinical Trials Cytokine Receptors Development Elements Endothelial Cells Event Functional disorder Heart failure Hypertension Hypothalamic structure Inflammation Inflammatory Inflammatory Response Interleukins Intracarotid Laboratories Learning Lesion Low Cardiac Output Measures Mediating Modeling Molecular Nerve Neuraxis Neuroglia Neurons Neurosecretory Systems Obesity Organ Pathogenesis Peripheral Pharmaceutical Preparations Plasma Process Production Prosencephalon Rattus Reactive Oxygen Species Receptor, Angiotensin, Type 1 Renin-Angiotensin System Role Severities Signal Transduction Sodium Source Subfornical Organ Sympathetic Nervous System Synapses Systemic Therapy Systolic heart failure Techniques Therapeutic Therapeutic Intervention Thirst Tumor Necrosis Factor-alpha Up-Regulation Work adverse outcome cyclooxygenase 2 cytokine endoplasmic reticulum stress hemodynamics in vivo increased appetite insight interest intravenous administration intravenous injection macrophage neurochemistry paraventricular nucleus pressure public health relevance receptor response socioeconomics therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Systolic heart failure (HF) is a devastating condition with high socioeconomic impact. Progress in the development of new pharmacological agents to treat HF is stagnant. Standard therapy targets the untoward peripheral effects of the heightened activity of the renin-angiotensin- system (RAS) and sympathetic nervous system (SNS), compensatory mechanisms that seek to maintain pressure in the face of a low cardiac output. As yet, there is no specific therapy for the inflammatory state that accompanies HF and contributes to adverse outcomes. Large clinical trials demonstrated no benefit of anti-cytokine agents, which can have serious side effects. Recent studies have revealed that the central nervous system actions of pro-inflammatory cytokines (PICs) contribute to the pathogenesis of HF - in particular, to the detrimental increase in sympathetic nerve activity. That work has focused almost exclusively on the effects of PICs inside the blood-brain barrier (BBB), with little attention to the effects of circulating PICs that reflect the peripheral inflammatory state but are too large to cross the BBB. Our preliminary studies demonstrate that blood-borne PICs act upon the subfornical organ (SFO), a forebrain circumventricular organ that lacks a BBB, to increase sympathetic activity in normal rats. We hypothesize that the high circulating levels of PICs in HF induce an inflammatory/excitatory state in the SFO that drives inflammatory/excitatory mechanisms downstream in the hypothalamic paraventricular nucleus (PVN) to increase peripheral sympathetic nerve activity. Since PIC receptors mediate molecular rather than synaptic events, their effects on the SFO are likely mediated by upregulation of intracellular signaling mechanisms related to RAS, reactive oxygen species, and endoplasmic reticulum stress. The proposed studies will: 1) determine the contribution of tumor necrosis factor (TNF)-a and interleukin (IL)-1b, acting upon their receptors in SFO, to sympathetic excitation in normal rat and rats with HF; 2) identify the cellular and molecular mechanisms activated in the SFO by TNF-a and IL-1b, and their impact on cellular and molecular mechanisms downstream in PVN; 3) determine whether counteracting the effects of PICs at the SFO level is a viable potential therapeutic strategy to reduce sympathetic excitation and its consequences in HF. A combination of molecular, immunohistochemical, and in vivo electrophysiological and hemodynamic recording techniques will be used to elucidate the mechanisms by which blood-borne PICs, acting on the SFO, influence neurohumoral excitation. Since the SFO lacks a BBB, these studies may identify targets for therapeutic intervention in the inflammatory process in HF that are accessible to systemic drug administration.

描述（由申请人提供）：收缩性心力衰竭（HF）是一种具有巨大社会经济影响的毁灭性状况。新的药理学剂治疗HF的开发进展停滞不前。标准疗法的目标是肾素 - 血管紧张素系统（RAS）和交感神经系统（SNS）的活动增强活动的不良外围作用，即面对低心输出量时，试图维持压力的补偿机制。到目前为止，伴随HF伴随的炎症状态尚无特定的疗法，并导致不良结果。大型临床试验表明，抗周围代因子没有任何好处，这可能会产生严重的副作用。最近的研究表明，促炎性细胞因子（PIC）的中枢神经系统作用有助于HF的发病机理 - 特别是交感神经活动的有害增加。这项工作几乎只关注血脑屏障内图片的影响（BBB），很少注意反映外围炎症状态但是循环图片的影响，但太大了，无法越过BBB。我们的初步研究表明，血液传播的照片作用于副构造器官（SFO），这是一种缺乏BBB的前脑室，以增加正常大鼠的交感神经活性。我们假设HF中的高循环水平在SFO中诱导炎症/兴奋状态，从而驱动下丘脑旁脑膜间核（PVN）下游的炎症/兴奋机制，以增加外围交感神经神经活性。由于PIC受体介导分子而非突触事件，因此它们对SFO的影响可能是通过上调与RAS，活性氧和内质网应激的上调的上调。拟议的研究将：1）确定肿瘤坏死因子（TNF）-A和白介素（IL）-1b的贡献，作用于SFO的受体对正常大鼠和HF大鼠的交感激发； 2）确定TNF-A和IL-1B在SFO中激活的细胞和分子机制，以及它们对PVN下游细胞和分子机制的影响； 3）确定在SFO水平上抵消图片的影响是否是减少交感神经激发及其在HF中的后果的可行潜在治疗策略。分子，免疫组织化学和体内电生理学和血液动力记录技术的结合将用于阐明对SFO作用的血传播图片影响神经肿瘤激发的机制。由于SFO缺乏BBB，因此这些研究可能会确定全身药物给药可使用的HF炎症过程中治疗性干预的靶标。