Ozone Cardiovascular Effects in Genetically Susceptible People

臭氧对遗传易感人群的心血管影响

• 批准号: 7887100
• 负责人: Mark Walter Frampton
• 金额: $ 33.01万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887100
• 关键词: Acute; Address; Affect; Air; Air Pollutants; Air Pollution; Antioxidants; Attention; Biological Availability; Blood Circulation; Blood Platelets; Blood Vessels; Blood Volume; Breathing; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chemicals; Clinical; Clinical Research; Coagulants; Crossover Design; Data; Double-Blind Method; Effectiveness; Endothelium; Epidemiologic Studies; Epithelium; Exercise; Exposure to; Free Radicals; Functional disorder; Future; Generations; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Screening; Glutathione S-Transferase; Heart Diseases; Hour; Human; Impairment; Inflammatory; Injury; Lipid Peroxidation; Lung; Measures; Modeling; Monitor; Morbidity - disease rate; Nitric Oxide; Nitrites; Nitrogen; Output; Oxidants; Oxidative Stress; Oxygen; Ozone; Particulate Matter; Pathway interactions; Patients; Perfusion; Peripheral; Predisposition; Preventive; Randomized; Research; Risk; Staging; Stroke Volume; Supplementation; Testing; Thrombosis; Tissues; Vascular Diseases; Vascular Endothelium; airway inflammation; base; capillary; design; dietary antioxidant; healthy volunteer; heart circulation; heart function; hemodynamics; innovation; mortality; novel strategies; nuclear factor-erythroid 2; ozone exposure; pollutant; primary outcome; public health relevance; pulmonary function; response; vasoconstriction; volunteer

DESCRIPTION (provided by applicant): Although there has been much research focused on the cardiovascular effects of particulate matter (PM) exposure, we know very little about the possible cardiovascular effects of the oxidant gaseous pollutant, ozone. We hypothesize that ozone exposure delivers an oxidative burden to the lung and to the vascular endothelium, via lipid peroxidation and secondary reactive oxygen and nitrogen species (ROS). This increased ROS burden depletes nitric oxide (NO) via chemical inactivation and reduced formation, altering vascular function in both the pulmonary and systemic circulations. Further, subjects with genetic polymorphisms conferring reduced function in glutathione transferase M1 (GSTM1) or nuclear factor erythroid 2- related factor 2 (Nrf2), key regulators of antioxidant defenses, will show increased susceptibility. In Aim #1, healthy nonsmoking subjects with and without genetic susceptibility will undergo 3 exposures: air, 0.1 ppm ozone, and 0.2 ppm ozone for 3 hours with intermittent exercise. The primary outcomes will be change in pulmonary and systemic vascular function, NO vascular bioavailability and transport, cardiac function, and platelet and microparticle activation. Airway inflammation and pulmonary function responses will also be assessed. Aim #2 will provide a new and innovative approach to the clinical study in Aim #1, determining the personal and ambient pollutant exposures of the subjects during their involvement in the study. We will incorporate personal monitoring of ozone and NO2, and data from central monitors on multiple pollutants, to assess subjects' exposures for 3 days prior, during, and 2 days after their experimental exposures. Analytical models will determine the influence of ambient pollutant exposures on the responses to the experimental exposures, and will incorporate both ambient and experimental exposures in an overall assessment of pollutant-related effects. We expect that subjects with the selected genetic polymorphisms in GSTM1 and Nrf2 will have increased systemic oxidative stress, reduced pulmonary capillary blood volume, and reduced peripheral vascular responsiveness and tissue perfusion in response to ozone exposure, and that these changes will correlate with the degree of airway inflammation. These studies will identify pathways and mechanisms for the cardiovascular effects of ozone exposure, identify determinants of susceptibility, and assist in establishing adequately protective ambient air quality standards. Confirmation of our hypothesis that subjects with impaired antioxidant defense are at increased risk will set the stage for future studies examining the effectiveness of preventive measures, such as dietary antioxidant supplementation. PUBLIC HEALTH RELEVANCE: Increases in air pollution are associated with increases in deaths from cardiovascular disease, but we know little about how ozone air pollution affects the cardiovascular system. Our proposed studies will determine the effects of ozone on blood vessel and heart function that could worsen illness in people with underlying heart disease. This will be accomplished by studying healthy volunteers who inhale ozone in a controlled clinical study, and also by studying their exposure to ozone and other pollutants during their normal daily activities. We will study volunteers who may be at increased risk for the effects of ozone because of genetic susceptibility. Understanding the effects of ozone on the heart and circulation can help establish appropriate air pollution standards, and provide strategies to protect the most susceptible people.

描述（由申请人提供）：虽然已经有很多研究集中在颗粒物（PM）暴露对心血管的影响上，但我们对氧化气体污染物臭氧可能对心血管的影响知之甚少。我们假设臭氧暴露通过脂质过氧化和二次活性氧和活性氮（ROS）给肺部和血管内皮带来氧化负担。这种增加的ROS负担通过化学失活和减少形成来消耗一氧化氮（NO），改变肺循环和体循环的血管功能。此外，基因多态性导致谷胱甘肽转移酶M1 （GSTM1）或核因子红细胞2相关因子2 (Nrf2)（抗氧化防御的关键调节因子）功能降低的受试者将表现出更高的易感性。在目标1中，有或没有遗传易感性的健康非吸烟受试者将接受3次暴露：空气、0.1 ppm臭氧和0.2 ppm臭氧，间歇运动3小时。主要结果将是肺和全身血管功能、NO血管生物利用度和运输、心功能以及血小板和微粒激活的变化。气道炎症和肺功能反应也将被评估。目标2将为目标1中的临床研究提供一种新的创新方法，确定受试者在参与研究期间的个人和环境污染物暴露。我们将结合个人对臭氧和二氧化氮的监测，以及来自中央监测仪的多种污染物的数据，评估受试者在实验暴露前3天、期间和之后2天的暴露情况。分析模型将确定环境污染物暴露对实验暴露反应的影响，并将环境和实验暴露纳入与污染物有关的影响的全面评估。我们预计，具有GSTM1和Nrf2遗传多态性的受试者在臭氧暴露下会增加全身氧化应激，减少肺毛细血管血容量，降低外周血管反应性和组织灌注，并且这些变化与气道炎症程度相关。这些研究将确定臭氧暴露对心血管影响的途径和机制，确定易感性的决定因素，并协助建立充分保护的环境空气质量标准。如果我们的假设得到证实，即抗氧化防御受损的受试者风险增加，将为未来研究检查预防措施的有效性奠定基础，例如饮食中补充抗氧化剂。