Cytokine-induced NeurohumoralExcitation in Heart Failure

心力衰竭中细胞因子诱导的神经体液兴奋

• 批准号: 7107952
• 负责人: JOSEPH FRANCIS
• 金额: $ 35.07万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107952
• 关键词: angiotensin receptor; cytokine; electrolyte balance; heart failure; interleukin 1; interleukin 6; laboratory mouse; laboratory rat; neural transmission; neurohormones; pathologic process; renin angiotensin system; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Chronic congestive heart failure is characterized by neurohumoral excitation (NHE) that contributes to the progression of end-stage disease and the premature demise of the patient. In the past few decades, most of the therapeutic measures were targeted against the activation of the neurohormonal system, and these strategies have clearly reduced mortality and morbidity. However, the clinical course of heart failure (HF) is progressive and the long-term prognosis remains dismal, suggesting that other mediators might be involved in NHE. Currently, immune mediated mechanisms have been recognized to play an important role in the pathogenesis of HF. Recently, we reported for the first time that cytokines are activated in the brain early after myocardial infarction. We also showed that blockade of cytokines attenuated NHE and angiotensin II receptor protein in the hypothalamus and the heart of HF rats. Therefore, we hypothesize that cytokines, acting either directly or via an interaction with the renin-angiotensin system (RAS), contribute to NHE in heart failure. The specific aims of this application are: 1. Peripheral cytokines drive NHE in heart failure, either directly or via an interaction with the peripheral RAS. 2. Central nervous system cytokines activate NHE in heart failure, either directly or via an interaction with products of intrinsic brain RAS. 3. Cardiac sympathetic afferents contribute to brain cytokine activation and bring about NHE in heart failure. This proposal will focus on understanding the contribution of peripheral and central nervous system influences of three cytokines (interleukin-1beta, tumor necrosis factor-alpha and interleukin-6) and angiotensin on NHE in HF. This will be accomplished by integrating a combination of molecular, cellular, electrophysiological and in vivo (rat and mouse model of HF) experimental approaches. The central link between cytokines and the neurohumoral system in HF may lead to a better understanding of the progression of the disease process and ultimately lead to new and effective strategies to treat HF.

描述（由申请人提供）：慢性充血性心力衰竭的特征是神经肿瘤激发（NHE），这些兴奋（NHE）有助于终阶段疾病的发展和患者的过早死亡。在过去的几十年中，大多数治疗措施都是针对神经激素系统激活的目标，这些策略显然降低了死亡率和发病率。但是，心力衰竭的临床过程是进行性的，长期预后仍然令人沮丧，这表明其他介体可能参与了NHE。当前，已经确认免疫介导的机制在HF的发病机理中起重要作用。最近，我们首次报道了心肌梗塞后早期在大脑中激活细胞因子。我们还表明，下丘脑和HF大鼠心脏中的NHE和血管紧张素II受体蛋白的阻断减弱了。因此，我们假设直接或通过与肾素 - 血管紧张素系统（RAS）的相互作用作用的细胞因子有助于心力衰竭。该应用的具体目的是：1。外周细胞因子直接或通过与外围RAS的相互作用驱动心力衰竭。 2。中枢神经系统细胞因子直接或通过与内在脑RAS产物的相互作用来激活心力衰竭。 3。心脏交感神经传入有助于脑细胞因子激活，并导致心力衰竭。该建议将集中于理解三种细胞因子（白介素-1Beta，肿瘤坏死因子-Alpha和interleukin-6）和HF血管紧张素的三种细胞因子（白介素1Beta，肿瘤坏死因子-Alpha和interleukin-6）的影响。这将通过整合分子，细胞，电生理学和体内（HF的大鼠和小鼠模型）实验方法的组合来实现。 HF中细胞因子与神经肿瘤系统之间的核心联系可能会更好地了解疾病过程的进展，并最终导致治疗HF的新策略。