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，以及特定的挑战主题04-ES-102：使用受控的人类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)对于心血管效应可能特别重要，因为它们具有高比表面积和活性表面化学，有可能将活性氧物种(ROS)输送到肺和血管空间。该项目将结合血管和心脏功能的生理指标与一氧化氮(NO)生物利用度和运输的新标记物来检验以下假设：1.环境UFP暴露损害肺和全身血管功能，部分是通过改变NO的运输和生物利用度。2.选择的氧化防御基因的功能障碍增加了UFP对肺和心血管影响的易感性。3.在易感人群中，UFP对肺和心血管的影响将与全身氧化应激的标志物和UFP氧化潜能有关。目的：进行一项人体临床暴露研究，检测2个抗氧化剂基因功能减退和不减退的健康受试者对周围UFP的肺和心血管反应。我们的方法将是进行一项随机、双盲、两个周期的交叉临床研究，研究暴露于浓缩的环境UFP和清洁的过滤空气中。我们将研究三组受试者，每组12人，不同的基因类型如下：1)GSTM1缺失，2)Nrf2-617A/C，以及3)这两个基因的“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容量的变化和外周血白细胞黏附分子表达的变化来评估。将使用血压和心率、前臂体积描记术和反应性充血、血小板激活和循环微粒来评估全身血管功能。通过测量动脉/静脉亚硝酸盐、FeNOHb和SNOHb的梯度，将检验我们的假设，即没有生物利用度和转运参与对血管功能的影响。心功能将使用心阻抗图(ICG)进行无创性评估。将通过测量肺内NO交换来评估呼吸道炎症。我们将检测血浆和尿液中氧化应激/脂质过氧化的标志物。如果我们在候选SNPs的一个或两个受试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关系，我们的假设将得到支持。最后，我们希望看到UFP气溶胶的氧化潜力与生理效应之间的关系，这表明至少部分氧化应激是外源性的。这些研究将确定UFP暴露的心血管效应的易感性的途径、机制和遗传决定因素。 公共卫生相关性：空气颗粒物污染的增加与心血管疾病死亡人数的增加有关，但我们对这种情况是如何发生的，以及谁最容易受到影响知之甚少。我们拟议的研究将确定非常小的(超细)室外空气污染颗粒物对基于遗传构成的易感性增加的人的血管和心脏功能的影响。无论有没有特定基因突变的健康志愿者，一次都会吸入室外浓缩的超细颗粒物，另一次则会净化空气。在暴露2小时之前和之后的48小时内，将对肺、血管和心脏功能进行详细测量，并对血液中的影响进行标记。我们预计在基因突变会增加易感性的受试者中会看到最强烈的影响。这些研究将有助于确定暴露在空气污染颗粒物中如何导致心脏和血管疾病，确定基因构成是否会影响易感性，并有助于制定保护最易受影响的人的策略。

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.