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: 7848221
• 负责人: Joel Daniel Kaufman
• 金额: $ 26.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7848221
• 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; Mus; 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; 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。最近的 观察结果表明，空气污染物，包括细颗粒和柴油排气（DE），触发 人类和动物模型中动脉反应性和血管收缩的增加。我们将使用吸入的DE 在临床环境中研究血管作用。假设是DE通过氧化发挥了血管作用 压力通过控制内皮和平滑肌的完善机制之一 电导容器，改变收缩和扩张的平衡。 首先，在人类受试者中，我们将测试臂动脉观察到的血管收缩反应是否 （使用超声）DE暴露后用抗氧化剂给药钝，并在 具有血管紧张素II易感性的个体（at。，受体变体AGTR1 A1166C）。这 相关的去诱导的可溶性介质（例如IL-6）和内皮激活标记的变化 例如内皮素-1也将被确定。 其次，我们将建立一个时间课程，以实现有关可溶性介质，内皮的事件 使用每个参数的串行研究以及基因的串行测量，激活和血管收缩 外周血单核细胞中的转录，并确定特定效应是否被AT阻断！ 受体阻滞剂Losartan。我们还将确定受试者的血管收缩效应是否增加 对于前肾上腺内皮素的基因编码中的常见SNP变体，一种已经相关的变体 具有高血压反应。 第三，我们将将研究与发现中心的其他项目密切相结合。我们将确定是否 在我们的人类研究中可以测试动物和体外模型中探索的假设。例如，我们将 确定DE是否增加了血浆ceruloplasmin和热休克蛋白的水平。我们还将创建一个 暴露于DE和FA的配对人类样品的存储库，以进行其他分析，并与 培养研究中的人类细胞。 研究利用临床和基本科学家之间的伙伴关系来探索关键机制 这种环境引起的疾病的基础。我们将得出对空气原因的理解 与污染物相关的心血管疾病。需要此信息来发展预防和治疗 策略。