Ozone Cardiovascular Effects in Genetically Susceptible People

描述(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，但我们对氧化性气体污染物臭氧可能对心血管造成的影响知之甚少。我们假设，臭氧暴露通过脂质过氧化和次级活性氧和氮物种(ROS)向肺和血管内皮细胞传递氧化负担。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)，改变肺和体循环中的血管功能。此外，具有谷胱甘肽转移酶M1(GSTM1)或核因子红系相关因子2(NRF2)功能降低的基因多态的受试者将表现出更高的易感性，这是抗氧化防御的关键调节因素。在目标1中，有或没有遗传易感性的健康不吸烟受试者将经历3次暴露：空气、0.1ppm臭氧和0.2ppm臭氧，持续3小时并进行间歇运动。主要结果将是肺和全身血管功能的改变，没有血管的生物利用度和运输，心功能，以及血小板和微粒的激活。还将评估呼吸道炎症和肺功能反应。AIM#2将为AIM#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NO2的监测，以及中央监测器对多种污染物的数据，以评估受试者在实验暴露前、期间和之后3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，并将环境暴露和实验暴露纳入污染物相关影响的总体评估。我们预计，具有GSTM1和NRF2所选基因多态的受试者对臭氧暴露的反应将增加全身氧化应激，减少肺毛细血管血容量，降低外周血管反应性和组织灌注量，并且这些变化将与呼吸道炎症程度相关。这些研究将确定臭氧暴露对心血管的影响的途径和机制，确定易受影响的决定因素，并帮助建立充分保护环境空气质量标准。我们的假设得到证实，即抗氧化剂防御受损的受试者风险增加，这将为未来研究预防措施的有效性奠定基础，例如饮食中补充抗氧化剂。 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。我们提议的研究将确定臭氧对血管和心脏功能的影响，这可能会加剧潜在心脏病患者的疾病。这将通过在受控的临床研究中研究吸入臭氧的健康志愿者，以及通过研究他们在日常活动中暴露在臭氧和其他污染物中来实现。我们将研究那些可能因为遗传易感性而增加臭氧影响风险的志愿者。了解臭氧对心脏和循环的影响有助于制定适当的空气污染标准，并为保护最易受影响的人提供策略。

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.