Cytokine and sympathetic drive in heart failure

免疫系统激活(ISA)是公认的心力衰竭综合征的一个常见组成部分。促炎细胞因子肿瘤坏死因子-α(TNF-α)和白介素1-β(IL-1β)-ISA的血液传播产物-激活交感神经系统。这个项目的总体假设是，这些促炎细胞因子通过作用于下丘脑室旁核(PVN)的神经元，在心力衰竭中促进交感神经驱动的增强。对这一拟议效应的两个主要机制将进行调查。1)循环细胞因子诱导儿茶酚胺在PVN中的释放。PVN中儿茶酚胺含量的增加与其他病理生理条件下交感神经驱动的增强有关，如神经源性高血压。 肾素-血管紧张素系统(RAS)活性增加也是其特征。本研究将验证一种假说，即循环细胞因子引起的PVN中儿茶酚胺的释放激活交感兴奋的PVN神经元，并且这种作用是通过PVN中儿茶酚胺与RAS之间的相互作用来实现的。2)细胞因子诱导活性氧的产生。细胞因子可以在大脑中产生，并可能通过饱和的膜运输系统进入大脑。目前的研究将检验这一假说，即在心力衰竭时，PVN中细胞因子的存在会诱导ROS，从而激活交感兴奋的PVN神经元。最后，这些研究将检验 循环或内源性细胞因子激活PVN神经元的机制可能引起交感神经驱动的增加。最近的证据表明，从PVN发出的信号需要激活延髓头端腹外侧区(RVLM)的血管紧张素1型受体，以增加交感神经的驱动。目前的研究将确定由促炎细胞因子激活的交感兴奋PVN神经元是否利用这一途径。电生理记录技术将与多肽/递质释放的推拉分析和免疫组织化学相结合，在缺血性心力衰竭大鼠和假手术对照组中验证这些假说。这些研究将 为促炎细胞因子在心力衰竭中的作用提供重要的新见解。

Immune system activation (ISA) is a commonly recognized component of the heart failure syndrome. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-lbeta)- the blood borne products of ISA- activate the sympathetic nervous system. The overall hypothesis of this project is that these pro-inflammatory cytokines contribute to the augmented sympathetic drive in heart failure by their actions upon neurons in the paraventricular nucleus (PVN) of the hypothalamus. Two principal mechanisms for this proposed effect will be investigated. 1) Circulating cytokines induce catecholamine release in PVN. Increased catecholamine content in PVN has been associated with heightened sympathetic drive in other pathophysiologicalconditions, such as neurogenic hypertension, that are also characterized by increased activity of the renin-angiotensinsystem (RAS). The present studies will examine the hypothesis that catecholamine release in PVN, induced by circulating cytokines, activates sympatho-excitatory PVN neurons, and that this effect is facilitated by interactions in PVN between catecholamines and the RAS. 2) Cytokines induce the production of reactive oxygen species (ROS). Cytokines may be produced in the brain, and may enter the brain via a saturable membrane transport system. The present studies will examine the hypothesisthat in heart failure the presence of cytokines in the PVN induces ROS, which activates sympatho-excitatory PVN neurons. Finally, these studies will examine the mechanisms by which activation of PVN neurons by circulating or intrinsic cytokines might elicit an increase in sympathetic drive. Recent evidence suggests that signals descending from PVN require activation of an angiotensin type 1 receptor in rostral ventrolateral medulla (RVLM) to effect an increase in sympathetic drive. The present studies will determine whether sympatho-excitatoryPVN neurons activated by pro-inflammatory cytokines utilize this pathway. Electrophysiologicalrecordingtechniques will be used in conjunction with push-pull analysis of peptide/transmitter release and immunohistochemistry to test these hypotheses in rats with ischemia-induced heart failure and in sham-operated controls. These studies will provide important new insightsinto the role of the pro-inflammatorycytokines in heart failure.