Inhalation of Contaminated Mine Waste Dusts as a Route for Systemic Metal Toxicity

 描述(由申请人提供)：心血管和新陈代谢疾病在全国范围内呈上升趋势，越来越多的证据表明环境污染物作为附属心血管疾病(CVD)因素的作用。在新墨西哥州和纳瓦霍民族，许多废弃和未经修复的矿区仍然存在，并继续污染着土地、水和空气。在受影响的社区中，吸入采矿废物中富含金属的颗粒物(PM)可能会对心血管和肺部疾病构成未知的风险。空气中的颗粒物中的金属与心血管和肺的不良后果，特别是慢性炎症性血管疾病之间存在着强烈的联系。然而，许多毒理学研究都集中在金属的可溶形态上，这些金属与航运业中残油的燃烧更相关。在美国西南部的许多地方，采矿废物导致土壤受到严重的混合金属污染，导致铀(U)、铜(Cu)、钒(V)、镍(Ni)和砷(As)等元素的含量很高。我们将评估从有混合金属污染历史的社区获得的可吸入颗粒物对动脉粥样硬化的直接和间接影响。该工作模型与肺内复杂的相互作用有关，这些作用导致次级循环产物诱导血管内皮细胞炎症反应。免疫调节受体，如CD36、TLR4和氧化型低密度脂蛋白(LOX-1)的血凝素样受体(LOX-1)介导血管对空气污染的其他固体和气体成分的反应。金属在驱动血管先天免疫反应中的影响还知之甚少。我们假设，来自矿山废物污染部落地区的富含金属的PM肺暴露将产生循环因子，如氧化型低密度脂蛋白，这些循环因子反过来激活依赖于免疫调节受体的炎症反应和内皮细胞功能障碍。以下目标将以机械性和平移性的方式解决这一假设。在第一个目标中，我们将比较来自矿区的吸入粉尘样本在驱动全身血管毒性和血清炎症潜力方面的效力。在第二个目标中，我们将研究oxLDL和免疫调节受体在驱动内皮细胞活化和暴露于富含金属的PM引起的功能障碍中的作用我们将在体内和体外选择性地拮抗oxLDL/LOX-1途径，以评估内皮功能障碍和血管炎症的结果。最后，在第三个目标中，我们将在纳瓦霍队列中模拟顺风向暴露，以检查与血管内皮细胞损伤的循环标志物和血清炎症潜力的相关性。我们将模拟风尘暴露，并将其与炎症/内皮损伤标记物(oxLDL、可溶性ICAM和VCAM、内皮素-1)以及来自纳瓦霍民族252名成员的血清生物活性的结果联系起来。污染场地可修复PM对健康影响的表征将提供与危险识别和生物学合理性相关的重要信息，以支持风险管理和补救战略的优先顺序。

 DESCRIPTION (provided by applicant): Cardiovascular and metabolic diseases are on the rise nationally and a growing body of evidence highlights a role for environmental contaminants as adjunctive cardiovascular disease (CVD) factors. In New Mexico and the Navajo Nation, many abandoned and unremediated mining regions exist and continue to contaminate the land, water, and air. Inhalation of metal-rich particulate matter (PM) from mining waste may pose an unrecognized risk for cardiovascular and pulmonary disease in affected communities. A strong link exists between metals in airborne PM and adverse cardiovascular and pulmonary outcomes, especially chronic inflammatory vascular disease. However, much of the toxicology has focused on soluble forms of metal, which are more relevant to the burning of residual oil in the shipping industry. There are numerous sites in the Southwest US where mining waste has led to severe soil contamination of metals mixtures, leading to high levels of uranium (U), copper (Cu), vanadium (V), nickel (Ni), and arsenic (As), among others. We will assess direct and indirect atherogenic impacts of inhaled particulate matter obtained from communities with a history of mixed metals contamination. The working model relates to complex interactions in the lung that lead to secondary circulatory products that induce vascular endothelial inflammatory responses. Immunomodulatory receptors, such as CD36, TLR4, and the lechtin-like receptor for oxidized low-density lipoprotein (LOX-1) mediate vascular responses to other solid and gaseous components of air pollution. The impact of metals in driving vascular innate immune responses is poorly understood. We hypothesize that pulmonary exposures to metal-rich PM from mine waste-contaminated tribal regions will generate circulating factors such as oxidized LDL, which in turn activate inflammatory response and dysfunction in endothelial cells, dependent on immunomodulatory receptors. The following Aims will address this hypothesis in a mechanistic and translational manner. In the first Aim, we will compare the potency of inhaled dust samples from mining regions in terms of driving systemic vascular toxicity and serum inflammatory potential. In the second Aim, we will examine the role of oxLDL and immunomodulatory receptors in driving endothelial activation and dysfunction stemming from exposure to metal-rich PM. We will selectively antagonize the oxLDL/LOX-1 pathway in vivo and in vitro to assess outcomes of endothelial dysfunction and vascular inflammation. Lastly, in the third Aim we will model downwind exposures in a Navajo cohort to examine associations with circulating markers of endothelial injury and serum inflammatory potential. We will model windblown dust exposures and link to outcomes of inflammatory / endothelial injury markers (oxLDL, soluble ICAM and VCAM, endothelin-1) and serum bioactivity from a cohort of 252 members of the Navajo Nation. Characterization of health impacts of repairable PM from contaminated sites will provide important information related to hazard identification and biological plausibility to support prioritization of risk management and remediation strategies.