Cytokines and Sympathetic Activation in Heart Failure

描述（由申请人提供）：在心力衰竭患者中，循环中的促炎细胞因子如肿瘤坏死因子- α (TNF-a)和白细胞介素-1 β (IL-lb)的存在与疾病的严重程度直接相关，并预示着不良预后。促炎细胞因子已被证明可以激活下丘脑-垂体-肾上腺（HPA）轴并刺激交感神经系统。下丘脑管旁核（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（即皮质醇释放）的主要介质；交感肢体的调节机制尚不清楚。HPA轴的细胞因子激活是间接的：TNF-a和IL-lb刺激血管内皮上的受体释放前列腺素E2 (PGE2)， PGE2穿过血脑屏障，激发吻侧腹外侧髓质中含有去甲肾上腺素（NE）的神经元，进而刺激PVN中CRF的产生。该模型来源于对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增强心力衰竭的交感驱动。我们将设法确定：1)哪些神经递质物质（主要的候选物质是CRF、NE、PGE2）刺激PVN旁细胞神经元，进而激活脑干交感驱动中枢——主要的候选物质是CRF本身，刺激PVN中因应激而上调的CRF- r1受体，NE，它可以通过α -1肾上腺素能机制刺激PVN神经元，以及PGE2，我们最近已经证明，当直接注射到PVN中时，PGE2会引发类似于血源性TNF-a的反应；2)这些前交感副细胞PVN神经元是否通过上述HPA轴急性细胞因子刺激的经典途径在心力衰竭中被激活，或者通过其他机制，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内的促炎细胞因子可能驱动局部PGE2和CRF的产生以及神经末梢NE的释放。这些研究将在大鼠慢性缺血心力衰竭模型中进行，使用电生理，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.