Cytokines and Sympathetic Activation in Heart Failure

描述（由申请人提供）：在心力衰竭患者中，循环促炎细胞因子如肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1b）的存在与疾病的严重程度直接相关，并预示预后不良。 促炎细胞因子已被证明激活下丘脑-垂体-肾上腺（HPA）轴并刺激交感神经系统。 下丘脑室旁核（PVN）中的促肾上腺皮质激素释放因子（CRF）是该反应的体液分支的主要介质（即，皮质醇释放）;交感神经分支的介质未知。 HPA轴的细胞因子活化是间接的：TNF-α和IL-1b刺激血管内皮上的受体以释放前列腺素E2（PGE 2），其穿过血脑屏障以激发头端腹外侧延髓中含有去甲肾上腺素（NE）的神经元，其上升以刺激PVN中的CRF产生。 该模型来源于正常大鼠的急性研究。 该项目的总体假设是，促炎细胞因子的慢性刺激有助于心力衰竭中增强的交感神经驱动。 我们将努力确定：1）哪些神经递质物质（主要候选者是CRF、NE、PGE 2）刺激小细胞PVN神经元，其下降以激活脑干中的交感神经驱动中心-主要候选者是CRF本身，其刺激通过应激在PVN中上调的CRF-R1受体，NE，其可以通过α-1肾上腺素能机制刺激PVN神经元，和PGE 2，我们最近已经证明，当直接注射到PVN时，其引起类似于血液传播的TNF-α的反应; 2）这些前交感小细胞PVN神经元是否在心力衰竭中通过上述HPA轴的急性细胞因子刺激的经典途径被激活，或通过替代机制，例如我们最近在缺血性心力衰竭模型中观察到的局部下丘脑产生细胞因子;在后一种情况下，PVN内促炎细胞因子的存在可能驱动PGE 2和CRF的局部产生以及NE从神经末梢的释放。 这些研究将在大鼠慢性缺血性心力衰竭模型中进行，采用电生理学、免疫组织化学和分子技术。 这些研究将为促炎细胞因子在心力衰竭中的作用提供新的见解，可能导致新的治疗策略。

DESCRIPTION (provided by applicant): In patients with heart failure, the presence of circulating pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-a) and interleukin-1 beta (IL-lb) correlates directly with the severity of the disease and predicts a poor prognosis. The pro-inflammatory cytokines have been shown to activate the hypothalamicpituitary- adrenal (HPA) axis and stimulate the sympathetic nervous system. Corticotropin-releasing factor (CRF) in the paraventdcular nucleus of the hypothalamus (PVN) is the principal mediator of the humoral limb of this response (i.e., cortisol release); the mediator of the sympathetic limb is not known. Cytokine activation of the HPA axis is indirect: TNF-a and IL-lb stimulate receptors on the vascular endothelium to release prostaglandins E2 (PGE2), which crosses blood brain barrier to excite the norepinephrine (NE) containing neurons in rostral ventrolateral medulla that ascend to stimulate CRF production in PVN. This model has been derived from acute studies in normal rats. The overall hypothesis of this project is that chronic stimulation by pro-inflammatory cytokines contributes to the augmented sympathetic drive in heart failure. We will seek to determine: 1) which neurotransmitter substances (leading candidates being CRF, NE, PGE2) stimulate parvocellular PVN neurons that descend to activate centers of sympathetic drive in brain stem - leading candidates are CRF itself, exciting CRF-R1 receptors that are upregulated in PVN by stress, NE, which can excite PVN neurons via an alpha-1 adrenergic mechanism, and PGE2, which we have recently shown to elicit a response similar to blood-borne TNF-a when injected directly into PVN; 2) whether these presympathetic parvocellular PVN neurons are activated in heart failure over the classical pathway for acute cytokine stimulation of the HPA axis, described above, or by alternate mechanisms such as the local hypothalamic production of cytokines that we have recently observed in our ischemic heart failure model; in the latter case, presence of pro-inflammatory cytokines within the PVN might drive local production of PGE2 and CRF and release of NE from nerve terminals. These studies will be undertaken in a model of chronic ischemia-induced heart failure in rats, using electrophysiological, immunohistochemical and molecular techniques. These studies will provide new insights into the role of the pro-imflammatory cytokines in heart failure, perhaps leading to new therapeutic strategies.