Cardiovascular Effects of Particles:The Role of Oxidative Stress and Metal Pathw

描述(申请人提供)：自20世纪80年代末以来，对急性和慢性暴露于颗粒物空气污染的研究表明，颗粒物污染与过早死亡有关。很快就发现，这些早期死亡中的大多数都是由心血管疾病引起的。定义可能解释暴露在环境颗粒物中的心脏死亡/发病率的流行病学结果的潜在机制，定义颗粒物造成不良健康后果风险增加的亚群，以及了解不同类型颗粒物的不同毒性，这些都是美国国家研究委员会确定的研究重点。我们建议使用标准老龄化研究的数据来检验不同类型和来源的颗粒物暴露与心血管和肺反应之间的关系，这是一项由退伍军人管理局在大波士顿地区进行的前瞻性队列研究。具体地说，我们将检查以心率变异性为指标的自动功能的短期变化是否与粒子暴露有关，并通过检查改变对氧化应激和金属处理防御系统的基因的影响来确定这种影响是否部分由氧化应激和金属毒性介导。我们还将以无创性脉冲多普勒动脉顺应性和血压测量为指标，类似地检查血管功能的相关性和效果修改，并检查与炎症和氧化应激的系统标记物(C反应蛋白、SICAM、sVCAM、同型半胱氨酸和8-羟基鸟苷)的直接相关性。

DESCRIPTION (provided by applicant): Since the late 1980s, studies of acute and chronic exposure to particulate air pollution have shown it to be associated with early death. It was quickly apparent that most of these early deaths were from cardiovascular disease. Definition of the underlying mechanisms that may explain the epidemiological findings of cardiac mortality/morbidity associated with exposure to ambient particles, definition of subpopulation at increased risk of adverse health outcomes from particulate matter, and understanding the differential toxicity of different types of particles are among the research priorities defined by the U. S. National Research Council. We propose to examine the association of different types and sources of particle exposure with cardiovascular and pulmonary responses along a mechanistic pathway, using data from the Normative Aging Study, a prospective cohort study conducted by the Veterans Administration in the greater Boston area. Specifically, we will examine whether short term changes in automatic function, as indexed by heart rate variability, are associated with particle exposure, and determine whether that effect is mediated by part by oxidative stress and metal toxicity by examining effect modification by genotypes that modify defenses against oxidative stress and metal handling. We will similarly examine associations, and effect modification, for vascular function, as indexed by a non-invasive pulse Doppler measures of arterial compliance and blood pressure, and examine a direct association with systemic markers of inflammation and oxidative stress (c reactive protein, Sicam, Svcam, homocysteine, and 8-hydroxyguanosine.