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.

空气污染暴露与包括心肌梗塞在内的缺血性心脏病有关。最近 观测表明，空气污染物，包括细颗粒物和柴油机废气（DE）， 在人和动物模型中增加动脉反应性和血管收缩。我们将使用吸入式DE 在临床环境中研究血管效应。假设DE通过氧化作用发挥血管效应， 压力，通过一个完善的机制控制内皮细胞和平滑肌， 传导血管，改变收缩和扩张的平衡。 首先，在人类受试者中，我们将测试观察到的肱动脉血管收缩反应是否 （使用超声波）后DE暴露与抗氧化剂管理钝化，并提高 对血管紧张素II具有遗传易感性的个体（AT.，受体变体AGTR 1A 1166 C））。的 相关DE诱导的可溶性介质如IL-6和内皮活化标志物的变化 如内皮素-1也将被测定。 其次，我们将建立一个时间进程的事件发生方面的可溶性介质，内皮细胞 激活和血管收缩，使用每个参数的系列研究，以及基因的系列测量， 转录在外周血单核细胞，并确定是否特定的影响被阻断AT！ 受体阻断剂氯沙坦。我们还将确定DE的血管收缩作用是否在受试者中增加 在编码内皮素原的基因中有一个共同的SNP变异， 高血压反应。 第三，我们将把我们的研究与DISCOVER中心的其他项目紧密结合。我们将确定 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进行测试。比如我们会 确定DE是否增加血浆铜蓝蛋白和热休克蛋白水平。我们还将创建一个 暴露于DE和FA的配对人体样本储存库，用于额外分析和孵育 人类细胞培养研究。 这些研究利用临床和基础科学家之间的合作来探索关键机制 这种环境引发的疾病的根本原因。我们将了解空气的成因 与污染有关的心血管疾病。需要这些信息来制定预防和治疗措施。 战略布局