Mechanism of ambient particulate matter assosicated cardiovascular diseases: a fe

描述(由申请人提供)：已经有充分的文件证明，暴露在细颗粒物(PM2.5)中会导致人类心血管疾病(CVD)风险持续增加，其水平与美国目前的水平相同。然而，导致PM2.5相关心血管效应的机制(S)和成分(S)仍不清楚。在我们最近的亚慢性吸入研究中，我们观察到，在ApoE-/-小鼠模型中，与通常较低镍暴露浓度的日子相比，PM2.5含有较高浓度的镍(Ni)的日子，心率显著增加和心率变异性降低。我们进一步发现，在人类中，镍和钒最好地解释了城市间NMMAPS PM10死亡风险系数的变化。因此，我们假设镍是PM2.5相关心血管疾病的主要成分。然而，由于美国缺乏适当的人群同时暴露于PM2.5和镍，因此很难检验这一假设。最近，我们在中国发现了两个大城市，这两个城市暴露在环境PM2.5质量浓度相似的环境PM2.5中，但镍水平非常不同(金昌约500 ng Ni/m~3，张掖约10 ng Ni/m~3)。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记物研究，评估使用这些理想和独特的人群来研究镍在PM2.5相关心血管疾病中的潜在作用的可行性。这项研究的具体目的是：1)探讨对中国两个城市总体人群的心血管疾病死亡率和发病率进行时间序列分析的可行性，以确定镍在PM2.5相关心血管疾病中的潜在机制作用；2)确定是否可以使用常用的心血管生物标志物来评估镍在已确定人群中与PM2.5相关的心血管疾病中的作用。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)]和内皮功能障碍标志物(ICAM和VCAM)。这项研究将对一种极有可能导致心血管疾病的PM2.5成分的作用和作用机制提供深入的见解。这项研究应该对控制与环境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，是一种普遍存在的污染物，导致人类住院和心血管疾病(CVD)死亡人数持续增加，达到美国目前的水平。然而，PM导致心血管疾病的原因尚不清楚。这项研究旨在探讨镍在PM相关心血管疾病中可能扮演的角色。这项研究与主要的环境健康问题有关，应该对控制与环境PM暴露相关的健康危害的研究和立法法规具有重要意义。

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.