Cardiovascular Effects of Ultrafine Particles in Genetically Susceptible Subjects

描述（由申请人提供）：该申请涉及广泛的挑战领域（04）临床研究，以及特定的挑战主题，04- es -102：使用受控的人体暴露调查基因与环境的相互作用。环境颗粒物（PM）的增加与肺部和心血管疾病的发病率和死亡率有关。易感性的机制和遗传决定因素表明我们对PM空气污染对健康影响的理解存在空白。超细颗粒（UFP，直径<100 nm）由于其高比表面积和活性表面化学，具有将活性氧（ROS）输送到肺部和血管空间的潜力，在心血管效应方面可能特别重要。该项目将血管和心脏功能的生理测量与一氧化氮（NO）生物利用度和运输的新标志物相结合，以测试以下假设：环境UFP暴露损害肺和全身血管功能，部分通过改变NO运输和生物利用度。2. 某些氧化防御基因的功能障碍增加了UFP对肺部和心血管影响的易感性。3. 在易感受试者中，UFP对肺部和心血管的影响将与全身氧化应激标志物和UFP氧化电位有关。目的：开展一项人体临床暴露研究，检查两种抗氧化基因功能是否降低的健康受试者对环境UFP的肺和心血管反应。我们的方法将是进行一项随机、双盲、2期交叉临床研究，研究暴露于高浓度环境UFP和清洁、过滤的空气。我们将研究3组，每组12名受试者，不同的基因型如下：1)GSTM1 null, 2) Nrf2 -617A/C, 3)两个基因的“野生型”（GSTM1+和Nrf2 -617C/C）。暴露对肺血管功能的影响将通过测量肺毛细血管血容量的变化和外周血白细胞粘附分子表达的变化来评估。系统血管功能将通过血压和心率、前臂容积描记术和反应性充血、血小板活化和循环微粒来评估。我们的假设是NO的生物利用度和运输参与了血管功能的影响，我们将通过测量亚硝酸盐、FeNOHb和SNOHb的动脉/静脉梯度来检验。心功能将使用阻抗心动图（ICG）进行无创评估。通过测量肺NO交换来评估气道炎症。我们将测量血浆和尿液中氧化应激/脂质过氧化的标志物。如果我们在一个或两个具有候选snp的受试者组中发现肺或全身血管功能受损或心功能改变的证据，并且这些影响与氧化应激标志物之间存在正相关，那么我们的假设将得到支持。最后，我们期望看到UFP气溶胶的氧化电位与生理效应之间的关系，这表明至少一部分氧化应激是外源性的。这些研究将确定UFP暴露对心血管影响的易感性的途径、机制和遗传决定因素。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research, and specific Challenge Topic, 04-ES-102: Investigating gene x environment interaction using controlled human exposures. Increases in ambient particulate matter (PM) are associated with morbidity and mortality from pulmonary and cardiovascular disease. The mechanisms and genetic determinants of susceptibility represent gaps in our understanding of the health effects of PM air pollution. Ultrafine particles (UFP, <100 nm diameter) may be particularly important with regard to cardiovascular effects because of their high specific surface area and reactive surface chemistry, with potential to deliver reactive oxygen species (ROS) to the lung and vascular space. This project will combine physiologic measures of vascular and cardiac function with novel markers of nitric oxide (NO) bioavailability and transport to test the following hypotheses: 1. Ambient UFP exposure impairs pulmonary & systemic vascular function, in part by altering NO transport and bioavailability. 2. Dysfunction in selected oxidant defense genes increases susceptibility to the pulmonary and cardiovascular effects of UFP. 3. In susceptible subjects, UFP pulmonary and cardiovascular effects will be related to markers of systemic oxidative stress, and to UFP oxidative potential. Aim: Conduct a human clinical exposure study examining pulmonary and cardiovascular responses to ambient UFP in healthy subjects with and without reduction in function of 2 antioxidant genes. Our approach will be to conduct a randomized, double-blind, 2-period crossover clinical study of exposure to concentrated ambient UFP and clean, filtered air. We will study 3 groups of 12 subjects each, with differing genotypes as follows: 1) GSTM1 null, 2) Nrf2 -617A/C, and 3) "wild type" for both genes (GSTM1+ and Nrf2 -617C/C). Effects of exposure on pulmonary vascular function will be assessed by measuring changes in pulmonary capillary blood volume and shifts in peripheral blood leukocyte adhesion molecule expression. Systemic vascular function will be assessed using blood pressure and heart rate, forearm plethysmography and reactive hyperemia, platelet activation, and circulating microparticles. Our hypothesis that NO bioavailability and transport are involved in the effects on vascular function will be tested by measuring arterial/venous gradients of nitrite, FeNOHb, and SNOHb. Cardiac function will be assessed noninvasively using impedance cardiography (ICG). Airway inflammation will be assessed by measuring pulmonary NO exchange. We will measure markers of oxidative stress/lipid peroxidation in plasma and urine. Our hypotheses will be supported if we see evidence for impaired pulmonary or systemic vascular function or altered cardiac function in one or both of the subject groups with the candidate SNPs, with a positive relationship between these effects and markers of oxidative stress. Finally, we expect to see a relationship between the oxidative potential of the UFP aerosol and physiologic effects, suggesting that at least a portion of the oxidative stress is exogenous. These studies will identify pathways, mechanisms, and genetic determinants of susceptibility for the cardiovascular effects of UFP exposure. PUBLIC HEALTH RELEVANCE: Increases in particulate air pollution are associated with increases in deaths from cardiovascular disease, but we know relatively little about how this happens, and who is most susceptible. Our proposed studies will determine the effects of very small (ultrafine) outdoor air pollution particles on blood vessel and heart function in people who may have increased susceptibility based on their genetic makeup. Healthy volunteers with and without specific gene mutations will inhale concentrated outdoor ultrafine particles on one occasion, and clean air on another occasion. Detailed measurements of lung, blood vessel, and heart function, and markers of effects in the blood, will be made before and at intervals up to 48 hours after the 2- hour exposure. We expect to see the strongest effects in the subjects with gene mutations that increase susceptibility. These studies will help determine how exposure to air pollution particles contributes to heart and vascular disease, determine whether genetic makeup affects susceptibility, and help to develop strategies to protect the most susceptible people.