Endothelial Oxidative Stress and Inflammation:Mechanisms and Human Studies

内皮氧化应激和炎症：机制和人体研究

• 批准号: 7783700
• 负责人: PAOLO C COLOMBO
• 金额: $ 40.18万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783700
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Blood Pressure; Blood Vessels; Chronic; Clinical; Coupled; Data; Development; Disease; Economic Inflation; Endocrine; Endothelial Cells; Endothelium; Equation; Event; Excision; Experimental Models; Financial compensation; Functional disorder; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genome; Health; Healthcare; Heart Diseases; Heart failure; Hospitalization; Hospitals; Hour; Human; Immunofluorescence Immunologic; Individual; Inflammation; Inflammatory; Kidney Failure; Link; Measures; Medicine; Messenger RNA; Methods; Microarray Analysis; Modeling; Molecular; Morbidity - disease rate; Neurohormones; Organ; Oxidative Stress; Pathway interactions; Patients; Peripheral; Plasma; Prevention; Protein Analysis; Proteins; Public Health; Randomized; Reactive Oxygen Species; Recording of previous events; Research; Resolution; Resources; Role; Sampling; Series; Side; Stimulus; Stretching; Symptoms; Techniques; Testing; Therapeutic; Time; Translating; Ultrafiltration; United States National Institutes of Health; Up-Regulation; Vascular Endothelium; Veins; Venous; Venous Pressure level; arm; base; design; hemodynamics; in vivo; minimally invasive; mortality; novel; paracrine; programs; protein expression; public health relevance; response; therapy design

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is a systemic inflammatory disease characterized by endothelial dysfunction and neurohormonal activation. Patients with chronic heart failure (CHF) consume a large percentage of health care resources as they are frequently hospitalized for acute decompensated heart failure (ADHF) based on clinical evidence of venous congestion. Accumulating evidence suggests that (i) venous congestion is a major predictor of morbidity and mortality in ADHF; and (ii) venous congestion begins to occur weeks before symptoms worsen resulting in a need for urgent in-hospital therapy. Despite this clinical evidence suggesting a role for venous congestion in the pathophysiology of ADHF, the biomechanically-driven effects of venous congestion on the vascular endothelium (the largest endocrine/paracrine organ of the body) and on neurohormonal activation remain unexplored. Our preliminary data using a novel, safe method of venous endothelial sampling coupled with analysis of protein and gene expression, indicate that: (i) clinical congestion, in patients hospitalized for ADHF, is associated with endothelial activation of the oxidative/inflammatory programs; and, mechanistically, (ii) that experimental congestion, in normal subjects, is sufficient to promote endothelial and neurohormonal activation. The central hypothesis of the proposed research is that venous congestion, in patients with CHF, acts as an independent oxidative/inflammatory stimulus which modulates key genetic regulatory events related to endothelial and neurohormonal activation, and, thereby, to the development and the resolution of ADHF. We propose to investigate this hypothesis using a two-pronged design which will allow us to study "volume- sensitive" genes and proteins, and global gene expression in endothelial cells, as well as neurohormonal activity in plasma in response to both (i) acute experimental congestion among n=24 compensated, euvolemic CHF patients with no recent history of ADHF, as well as among n=24 compensated patients with recent history of ADHF (Aim 1); and, conversely (ii) acute therapeutic decongestion, by "high" volume vs. "standard" volume ulltrafiltration, among n=48 patients hospitalized for ADHF with clinical evidence of venous congestion (Aim 2). In 2007, the NIH identified inflammation as "a key area of public health in need of broad-based collaborative research". If successful, our studies (i) will model the biomechanically-driven pathways that initiate and sustain inflammation in veins and thereby contribute to the clinical transition from compensation to acute decompensation in CHF; and, on the other side of the equation, (ii) will uncover those anti-oxidant/anti- inflammatory cascades that contribute to the prevention and/or resolution of ADHF. Overall, our data may provide a strong rationale for future studies that will use a molecular-based approach, in the unique individual, for the prevention and treatment of ADHF. PUBLIC HEALTH RELEVANCE: Chronic heart failure (CHF) is a major health problem; a systemic rather than only cardiac disorder characterized by vascular and neurohormonal derangement. Patients with CHF are responsible for consuming a large percentage of the health care resources as they are frequent hospitalized for acute decompensation. The results of this study will help elucidate the vascular and neurohormonal events that sustain clinical compensation and/or promote resolution of decompensation in the unique CHF patient, thus paving the way to more predictive and personalized medicine.

描述（申请人提供）：慢性心力衰竭（CHF）是一种以内皮功能障碍和神经激素激活为特征的全身炎症性疾病。慢性心力衰竭 (CHF) 患者消耗了大量的医疗保健资源，因为根据静脉充血的临床证据，他们经常因急性失代偿性心力衰竭 (ADHF) 住院。越来越多的证据表明，(i) 静脉充血是 ADHF 发病率和死亡率的主要预测因素； (ii) 在症状恶化前几周开始出现静脉充血，导致需要紧急住院治疗。尽管临床证据表明静脉充血在 ADHF 的病理生理学中发挥作用，但静脉充血对血管内皮（身体最大的内分泌/旁分泌器官）和神经激素激活的生物力学驱动作用仍有待探索。 我们使用一种新颖、安全的静脉内皮取样方法并结合蛋白质和基因表达分析得到的初步数据表明：(i) 因 ADHF 住院的患者的临床充血与氧化/炎症程序的内皮激活有关；并且，从机制上讲，（ii）正常受试者中的实验性充血足以促进内皮细胞和神经激素的激活。该研究的中心假设是，CHF 患者的静脉充血作为一种独立的氧化/炎症刺激物，调节与内皮和神经激素激活相关的关键基因调控事件，从而调节 ADHF 的发生和缓解。 我们建议使用双管齐下的设计来研究这一假设，这将使我们能够研究“体积敏感”基因和蛋白质，以及内皮细胞中的整体基因表达，以及血浆中的神经激素活性，以响应（i）n = 24名近期无ADHF病史的代偿、血容量正常的CHF患者以及n = 24名近期有ADHF病史的代偿患者中的急性实验充血（目的 1）；相反，(ii) 在 n=48 名因 ADHF 住院且有静脉充血临床证据的患者中，通过“高”容量与“标准”容量超滤进行急性治疗性减充血（目标 2）。 2007年，美国国立卫生研究院将炎症确定为“需要广泛合作研究的公共卫生关键领域”。如果成功，我们的研究 (i) 将模拟启动和维持静脉炎症的生物力学驱动途径，从而有助于 CHF 从代偿到急性失代偿的临床转变；另一方面，(ii) 将揭示那些有助于预防和/或解决 ADHF 的抗氧化/抗炎级联反应。总体而言，我们的数据可能为未来的研究提供强有力的依据，这些研究将在独特的个体中使用基于分子的方法来预防和治疗 ADHF。 公共卫生相关性：慢性心力衰竭 (CHF) 是一个主要的健康问题；一种以血管和神经激素紊乱为特征的全身性疾病，而不仅仅是心脏疾病。慢性心力衰竭患者经常因急性失代偿而住院，因此消耗了大量的医疗资源。这项研究的结果将有助于阐明维持临床代偿和/或促进独特CHF患者失代偿解决的血管和神经激素事件，从而为更具预测性和个性化的医疗铺平道路。