Ozone Cardiovascular Effects in Genetically Susceptible People

描述（由申请人提供）：虽然有很多研究集中在颗粒物（PM）暴露对心血管的影响上，但我们对氧化剂气态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次级活性氧和氮物质（ROS）向肺和血管内皮提供氧化负荷。这种增加的ROS负荷通过化学失活和减少形成来消耗一氧化氮（NO），从而改变肺循环和体循环中的血管功能。此外，具有赋予谷胱甘肽转移酶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）功能降低的遗传多态性的受试者将显示出增加的易感性。在目标#1中，有和没有遗传易感性的健康非吸烟受试者将经历3次暴露：空气、0.1 ppm臭氧和0.2 ppm臭氧，持续3小时，并进行间歇性运动。主要结局将是肺和全身血管功能的变化、NO血管生物利用度和转运、心脏功能以及血小板和微粒活化。还将评估气道炎症和肺功能反应。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。我们将结合臭氧和NO2的个人监测，以及来自中央监测器的多种污染物的数据，以评估受试者在实验暴露前3天、暴露期间和暴露后2天的暴露。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有关的影响的全面评估。我们预计，GSTM 1和Nrf2基因多态性的受试者将增加全身氧化应激，减少肺毛细血管血容量，减少外周血管反应性和组织灌注，以响应臭氧暴露，这些变化将与气道炎症的程度。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，并协助制定充分保护性的环境空气质量标准。我们假设抗氧化防御受损的受试者风险增加，这一假设的证实将为未来研究预防措施（如膳食抗氧化剂补充剂）的有效性奠定基础。 公共卫生相关性：空气污染的增加与心血管疾病死亡的增加有关，但我们对臭氧空气污染如何影响心血管系统知之甚少。我们提出的研究将确定臭氧对血管和心脏功能的影响，这些影响可能会使患有潜在心脏病的人的疾病恶化。这将通过研究在对照临床研究中吸入臭氧的健康志愿者，以及研究他们在正常日常活动中暴露于臭氧和其他污染物来实现。我们将研究那些由于遗传易感性而可能受到臭氧影响的风险增加的志愿者。了解臭氧对心脏和循环的影响有助于建立适当的空气污染标准，并提供保护最易感人群的策略。

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.