Cytokines and Sympathetic Activation in Heart Failure

描述（由申请人提供）：收缩期心力衰竭（HF）是一种具有高度社会经济影响的破坏性疾病。治疗心衰的新药物开发进展停滞不前。标准治疗针对肾素-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，这是在低心输出量时寻求维持压力的代偿机制。到目前为止，对于伴有心衰并导致不良结果的炎症状态，还没有专门的治疗方法。大型临床试验表明，抗细胞因子药物没有任何益处，它可能有严重的副作用。最近的研究表明，促炎细胞因子（PICs）的中枢神经系统作用有助于HF的发病机制-特别是交感神经活动的有害增加。这项工作几乎完全集中在血脑屏障（BBB）内PICs的影响上，几乎没有

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.