Cytokines and Sympathetic Activation in Heart Failure

心力衰竭中的细胞因子和交感神经激活

• 批准号: 6671631
• 负责人: Robert B Felder
• 金额: $ 46.25万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671631
• 关键词: corticotropin releasing factor; cytokine; electrophysiology; heart failure; hypothalamic pituitary adrenal axis; immunocytochemistry; laboratory rat; neural initiation; neuroimmunomodulation; neurotransmitter metabolism; norepinephrine; paraventricular nucleus; prostaglandin E; sympathetic nervous system

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.

描述（由申请人提供）：在心力衰竭的患者中，循环促炎性细胞因子（如肿瘤坏死因子因子-Alpha（TNF-A）（TNF-A）和白介素-1β（IL-LB）的存在直接与疾病的严重程度直接相关，并预测了较差的预后。 促炎性细胞因子已被证明可以激活下丘脑 - 肾上腺肾上腺（HPA）轴并刺激交感神经系统。 在下丘脑（PVN）的副核核中，皮质激素释放因子（CRF）是该反应的体液肢体的主要介体（即皮质醇释放）；交感神经的介体尚不清楚。 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. 该模型是从正常大鼠中的急性研究得出的。 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的增强交感神经驱动。 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，我们最近证明，当直接注射到PVN中时，它会引起类似于血液传播的TNF-A的反应； 2）在上面描述的HPA轴急性细胞因子刺激的经典途径上，这些先前交感神经PVN神经元是否在心力衰竭中激活，或通过替代机制（例如局部的细胞因子下丘脑产生的细胞因子生产，我们最近在我们的缺血性心力衰竭模型中都观察到的；在后一种情况下，PVN中存在促炎性细胞因子可能会驱动PGE2和CRF的局部产生，以及从神经末端释放NE。 这些研究将在使用电生理，免疫组织化学和分子技术的大鼠慢性缺血诱导的大鼠心力衰竭的模型中进行。 这些研究将为促炎性细胞因子在心力衰竭中的作用提供新的见解，也许会导致新的治疗策略。