Cytokines and Sympathetic Activation in Heart Failure

心力衰竭中的细胞因子和交感神经激活

• 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
• 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

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(申请人提供)：收缩性心力衰竭(HF)是一种破坏性的疾病，具有很高的社会经济影响。治疗心力衰竭的新药的开发进展停滞不前。标准疗法针对肾素-血管紧张素系统(RAS)和交感神经系统(SNS)活动增强的不良外周效应，这是一种在低心输出量时寻求保持血压的代偿机制。到目前为止，还没有针对伴随心力衰竭并导致不良结果的炎症状态的特效治疗方法。大型临床试验表明，抗细胞因子药物没有任何益处，因为它可能会有严重的副作用。最近的研究表明，促炎症细胞因子(PIC)的中枢神经系统活动参与了HF的发病，尤其是交感神经活动的有害增加。这项工作几乎完全集中在血脑屏障(BBB)内图片的影响上，几乎没有什么 注意循环图片的影响，这些图片反映了周围炎症状态，但 太大了，不能越过BBB。我们的初步研究表明，血液传播的PIC作用于穹隆下器(SFO)，这是一种缺乏血脑屏障的前脑室周器官，可以增加正常大鼠的交感神经活动。我们假设，在HF中，高水平的PIC在SFO中诱导炎症/兴奋状态，从而驱动下丘脑室旁核(PVN)下游的炎症/兴奋机制，从而增加外周交感神经活动。由于PIC受体介导的是分子而不是突触事件，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相关的细胞内信号机制来实现的。拟进行的研究将：1)确定作用于SFO中其受体的肿瘤坏死因子-a和白介素1b对正常大鼠和心力衰竭大鼠交感兴奋的作用；2)确定肿瘤坏死因子-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水平上对抗PICS的作用是否是一种可行的潜在治疗策略，以减少交感兴奋及其在心力衰竭中的后果。结合分子、免疫组织化学、体内电生理和血流动力学记录技术，将阐明作用于SFO的血源性PIC影响神经体液兴奋的机制。由于SFO缺乏血脑屏障，这些研究可能确定可用于治疗干预心衰炎症过程的靶点，这些靶点可用于全身用药。