Project 1: Vascular Response to Diesel Exhaust in Humans

项目 1：人体对柴油机尾气的血管反应

• 批准号: 8278529
• 负责人: Joel Daniel Kaufman
• 金额: $ 32.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278529
• 关键词: Acetylcysteine; Acute; Air Pollutants; Air Pollution; Angiotensin II; Angiotensin Receptor; Animal Model; Animals; Antioxidants; Attenuated; Behavior; Biological Markers; Blood Vessels; Breathing; Cardiovascular Diseases; Cell Culture Techniques; Cell model; Cells; Ceruloplasmin; Clinical; Code; Coronary artery; Diesel Exhaust; Disease; Endothelin-1; Endothelium; Epidemiologic Studies; Equilibrium; Event; Exposure to; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Heat shock proteins; Hour; Human; In Vitro; Individual; Inflammation Mediators; Interleukin-6; Kinetics; Link; Losartan; Measurable; Measures; Mediator of activation protein; Modeling; Molecular; Molecular Profiling; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Particulate; Particulate Matter; Pathway interactions; Peripheral Blood Mononuclear Cell; Physiological; Plasma; Preproendothelin; Prevention; Production; RNA; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Resolution; Sampling; Scientist; Series; Smooth Muscle; Smooth Muscle Myocytes; Supplementation; Testing; Therapeutic; Time; Tissue Sample; Tissues; Toxicogenomics; Ultrasonography; Urine; Variant; Work; air filter; ascorbate; base; brachial artery; constriction; cytokine; exposed human population; free radical oxygen; gene therapy; genetic variant; human subject; human tissue; in vitro Model; insight; intervention effect; mouse model; receptor; repository; research study; response; time use; trafficking; vasoconstriction

Air pollution exposures are associated with ischemic heart diseases including myocardial infarction. Recent observations demonstrate that air pollutants, including fine particulate and diesel exhaust (DE), trigger increased arterial reactivity and vasoconstriction in both human and animal models. We will use inhaled DE to study vascular effects in a clinical setting. The hypothesis is that DE exerts vascular effects via oxidative stress, through one of the well-established mechanisms controlling endothelium and smooth muscle in conductance vessels, altering the balance of constriction and dilation. First, in human subjects, we will test whether the observed vasoconstrictive response in the brachial artery (using ultrasound) following DE exposure is blunted with antioxidant administration, and heightened in individuals with genetic susceptibility to angiotensin II (AT., receptor variant AGTR1 A1166C)). The associated DE-induced changes in soluble mediators such as IL-6, and markers of endothelial activation such as endothelin-1 will be also be determined. Second, we will establish a time course for events occurring with regard to soluble mediators, endothelial activation, and vasoconstriction, using serial studies of each parameter, as well as serial measures of gene transcription in peripheral blood mononuclear cells, and determine if specific effects are blocked by the AT! receptor blocker losartan. We will also determine if DE's vasoconstrictive effects are increased in subjects with a common SNP variant in the gene coding for preproendothelin, a variation which is already associated with hypertensive responses. Third, we will closely integrate our studies with other projects in the DISCOVER Center. We will determine if hypotheses explored in animal and in vitro models can be tested in our human studies. For example, we will determine if DE increases plasma levels of ceruloplasmin and Heat Shock Protein. We will also create a repository of paired human samples exposed to DE and FA, for additional analyses and for incubation with human cells in culture studies. The studies exploit a partnership between clinical and basic scientists to explore the key mechanisms underlying this environmentally-induced disease. We will derive an understanding of the causes of air pollutant-related cardiovascular disease. This information is needed to develop prevention and therapeutic strategies.

接触空气污染与包括心肌梗死在内的缺血性心脏病有关。近期 观察表明，空气污染物，包括细颗粒物和柴油废气(DE)，会引发 在人类和动物模型中增加动脉反应性和血管收缩。我们将使用吸入性DE 在临床环境中研究血管效应。假说是DE通过氧化作用发挥血管效应 应激，通过一种成熟的机制来控制血管内皮细胞和平滑肌 传导血管，改变收缩和扩张的平衡。 首先，在人类受试者身上，我们将测试观察到的臂动脉血管收缩反应 (使用超声波)DE暴露后，给予抗氧化剂使其钝化，并在 具有血管紧张素II遗传易感性的个体(AT，受体变异体AGTR1 A1166C)。这个 DE诱导的可溶性介质如IL-6和内皮激活标志物的相关变化 如内皮素-1也将被测定。 其次，我们将建立与可溶性介质、内皮细胞相关的事件发生的时间进程 激活和血管收缩，使用对每个参数的连续研究以及对基因的连续测量 在外周血单核细胞中转录，并确定特定的作用是否被AT！ 受体阻滞剂氯沙坦。我们还将确定DE的血管收缩作用是否在受试者中增加 在编码前内皮素的基因中有一个常见的SNP变异，这个变异已经与 有高血压反应。 第三，我们将把我们的研究与探索中心的其他项目紧密结合起来。我们将确定是否 在动物和体外模型中探索的假设可以在我们的人类研究中得到检验。例如，我们将 确定DE是否会增加血浆铜蓝蛋白和热休克蛋白的水平。我们还将创建一个 暴露在DE和FA中的成对人类样本的储存库，用于其他分析和与 培养研究中的人体细胞。 这些研究利用临床和基础科学家之间的合作来探索关键的机制 是这种环境引起的疾病的潜在原因。我们将对空气的成因有一个了解 与污染物相关的心血管疾病。这些信息是开发预防和治疗所必需的 战略。