Mechanism of ambient particulate matter assosicated cardiovascular diseases: a fe

描述（由申请人提供）：有充分的证据表明，暴露于细空气颗粒物（PM2.5）会导致人类心血管疾病（CVD）的风险持续增加，目前在美国遇到的水平。然而，PM2.5相关心血管影响的机制和成分仍然未知。在我们最近的亚慢性吸入研究中，我们观察到ApoE-/-小鼠模型中，PM2.5中镍（Ni）浓度升高的日子与典型的低镍暴露的日子相比，心率急剧增加和心率变异性下降。我们进一步发现，在人类中，镍和钒最能解释NMMAPS PM10死亡率风险系数在城市之间的变化。因此，我们假设Ni是PM2.5相关CVD的主要组成部分。然而，由于美国缺乏适当的PM2.5和Ni暴露组合的适当人群，因此很难验证这一假设。最近，我们确定了中国的两个大城市，它们暴露于相似的环境PM2.5质量浓度，但Ni水平非常不同（金昌的~500ng Ni/m3和张掖市的~ 10ng Ni/m3）。因此，我们建议通过基于人群的死亡率和发病率以及基于小组的生物标志物研究，评估使用这些理想和独特人群来研究Ni在PM2.5相关心血管疾病中的潜在作用的可行性。本研究的具体目的是：1)探讨对中国两个城市总体人群CVD死亡率和发病率进行时间序列分析的可行性，以确定Ni在PM2.5相关CVD中的潜在机制作用；2)确定是否可以使用常用的CVD生物标志物来评估Ni在确定人群中PM2.5相关CVD中的作用。CVD的候选生物标志物包括促炎标志物[IL-6和C反应蛋白（CRP）]；白细胞募集标志物[单核细胞趋化蛋白1 (MCP-1)]；内皮功能障碍生物标志物（ICAM和VCAM）。本研究将深入了解极有可能诱发心血管疾病的PM2.5成分的作用和作用机制。这项研究应该对控制与环境中PM暴露相关的健康危害的研究和立法法规具有重要意义。公共卫生相关性：环境空气中的颗粒物（PM）是一种混合物，是一种无处不在的污染物，导致心血管疾病（CVD）的住院率和死亡率持续增加，目前在美国遇到的水平。然而，PM导致CVD的原因仍然未知。本研究旨在探讨镍在PM相关CVD中的作用。该研究与主要的环境健康问题有关，并应对控制与环境中PM接触有关的健康危害的研究和立法法规产生重大影响。

DESCRIPTION (provided by applicant): It has been well documented that exposure to fine ambient air particulate matter (PM2.5) induces consistent increased risk for cardiovascular disorders (CVD) in humans at the levels currently encountered in the U.S. However, the mechanism(s) and component(s) responsible for PM2.5 associated cardiovascular effects are still unknown. In our recent subchronic inhalation study, we observed that dramatic increases in heart rate and decreases in heart rate variability occurred in the ApoE-/- mouse model on days when PM2.5 contained elevated concentrations of nickel (Ni) as compared to days with typically lower Ni exposure. We further found in humans that Ni and vanadium best explained the variation of the NMMAPS PM10 mortality risk coefficients across cities. Therefore, we hypothesize that Ni is a major component responsible for PM2.5 associated CVD. It has been difficult, however, to test this hypothesis due to lack of appropriate populations with adequate combination of exposures to both PM2.5 and Ni in the U.S. Recently, we identified two large cities in China, which have exposures to similar ambient PM2.5 mass concentrations but very different levels of Ni (~500ng Ni/m3 in Jinchang and ~10 ng Ni/m3 in Zhanye). Therefore, we propose to evaluate the feasibility of using these ideal and unique populations to examine the potential roles of Ni in PM2.5 associated CVD through population- based mortality and morbidity and panel-based biomarker studies. The specific aims of the study are: 1) to examine the feasibility of conducting time-series analyses of CVD mortality and morbidity in the overall populations of the two Chinese cites to identify the potential mechanistic roles of Ni in PM2.5 associated CVD; 2) to determine whether or not the commonly used CVD biomarkers can be employed to evaluate the role of Ni in PM2.5 related CVD in the identified populations. The candidate biomarkers of CVD include proinflammatory markers [IL-6, and C reactive protein (CRP)]; markers of leukocyte recruitment [monocyte chemoattractant protein 1 (MCP-1)]; and endothelial dysfunction biomarkers (ICAM and VCAM). This study will provide insights into the role of, and mechanism for action of a highly likely PM2.5 component in terms of inducing CVD. This study should have significant implications for both research and legislative regulation in controlling the health hazards associated with ambient PM exposure. PUBLIC HEALTH RELEVANCE: Particulate matter (PM) in ambient air is a mixture and a ubiquitous pollutant that induces consistent increase in hospital admission and death of cardiovascular disorders (CVD) in humans at the levels currently encountered in the U.S. However, why PM causes CVD is still unknown. This study was proposed to address the role that nickel may play in PM associated CVD. The study is relevant to the major environmental health issues and should have significant implications for both research and legislative regulation in controlling the health hazards associated with ambient PM exposure.