Cytokines and Sympathetic Activation in Heart Failure

描述（由申请人提供）：充血性心力衰竭（HF）是一种具有高度社会经济影响的破坏性疾病。治疗HF的新药理学试剂的开发进展停滞不前。标准治疗针对的是肾素-血管紧张素系统（RAS）和交感神经系统（SNS）活性升高的不良外周效应，这些代偿机制在面对低心输出量时寻求维持压力。到目前为止，还没有特异性治疗伴随HF并导致不良结局的炎症状态。大型临床试验表明，抗细胞因子药物没有益处，可能有严重的副作用。最近的研究表明，促炎细胞因子（PIC）的中枢神经系统作用有助于HF的发病机制-特别是交感神经活性的有害增加。这项工作几乎完全集中在血脑屏障（BBB）内PIC的影响上， 注意循环PIC的影响，其反映外周炎症状态，但 太大了，无法穿过BBB。我们的初步研究表明，血液传播的PIC作用于穹窿下器官（SFO），一个前脑脑室周围器官，缺乏BBB，增加交感神经活动在正常大鼠。我们假设HF中PIC的高循环水平诱导SFO中的炎症/兴奋状态，其驱动下丘脑室旁核（PVN）中下游的炎症/兴奋机制以增加外周交感神经活动。由于PIC受体介导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传导机制介导的。拟议的研究将：1）确定TNF-α和IL-1b在正常大鼠和HF大鼠SFO中作用于其受体对交感兴奋的贡献：2）确定TNF-α和IL-1b激活SFO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水平抵消PIC的作用是否是减少HF中交感神经兴奋及其后果的可行的潜在治疗策略。分子，免疫组织化学，在体内电生理和血液动力学记录技术的组合将被用来阐明的机制，通过血液传播的PIC，作用于SFO，影响神经体液兴奋。由于SFO缺乏BBB，这些研究可能会确定全身药物给药可达到的HF炎症过程中的治疗干预靶点。

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.