Cardiovascular Effects of Ultrafine Particles in Genetically Susceptible Subjects

描述（由申请人提供）：本申请涉及广泛的挑战领域 (04) 临床研究，以及具体的挑战主题 04-ES-102：使用受控人体暴露来研究基因 x 环境相互作用。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相关。易感性的机制和遗传决定因素代表了我们对 PM 空气污染对健康影响的理解上的差距。超细颗粒（UFP，直径<100 nm）对于心血管影响可能特别重要，因为它们具有高比表面积和反应性表面化学性质，有可能将活性氧（ROS）输送到肺和血管空间。该项目将把血管和心脏功能的生理测量与一氧化氮 (NO) 生物利用度和转运的新型标志物结合起来，以测试以下假设： 1. 环境 UFP 暴露会损害肺和全身血管功能，部分是通过改变一氧化氮转运和生物利用度来实现的。 2. 特定氧化防御基因的功能障碍会增加对 UFP 肺部和心血管影响的易感性。 3. 在易感受试者中，UFP 的肺部和心血管影响将与全身氧化应激标志物和 UFP 氧化电位相关。目的：进行一项人体临床暴露研究，检查健康受试者对环境 UFP 的肺和心血管反应，无论其 2 种抗氧化基因的功能是否降低。我们的方法是对暴露于浓缩环境 UFP 和清洁过滤空气的情况进行随机、双盲、2 期交叉临床研究。我们将研究 3 组，每组 12 名受试者，具有如下不同的基因型：1) GSTM1 无效，2) Nrf2 -617A/C，以及 3) 两个基因（GSTM1 和 Nrf2 -617C/C）的“野生型”。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暴露对肺血管功能的影响。将使用血压和心率、前臂体积描记法和反应性充血、血小板活化和循环微粒来评估全身血管功能。我们假设 NO 的生物利用度和转运参与对血管功能的影响，将通过测量亚硝酸盐、FeNOHb 和 SNOHb 的动脉/静脉梯度来测试。将使用阻抗心动图（ICG）对心脏功能进行无创评估。通过测量肺部一氧化氮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 的受试者组中看到肺或全身血管功能受损或心脏功能改变的证据，并且这些效应与氧化应激标志物之间呈正相关，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途径、机制和遗传决定因素。 公共卫生相关性：颗粒物空气污染的增加与心血管疾病死亡人数的增加有关，但我们对这种情况如何发生以及谁最容易受到影响知之甚少。我们提出的研究将确定非常小的（超细）室外空气污染颗粒对根据其基因构成可能增加易感性的人群的血管和心脏功能的影响。有或没有特定基因突变的健康志愿者有时会吸入室外浓缩的超细颗粒，有时会吸入清洁空气。在 2 小时暴露之前和之后 48 小时内，将进行肺、血管和心脏功能的详细测量，以及血液中影响的标记。我们预计在具有增加易感性的基因突变的受试者中会看到最强烈的效果。这些研究将有助于确定接触空气污染颗粒如何导致心脏和血管疾病，确定基因组成是否影响易感性，并有助于制定保护最易受影响人群的策略。

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.