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

 描述（由申请人提供）：心血管和代谢疾病在全国范围内呈上升趋势，越来越多的证据强调了环境污染物作为心血管疾病（CVD）因素的作用。在新墨西哥州和纳瓦霍民族，许多废弃和未经整治的矿区存在，并继续污染土地，水和空气。采矿废物中富含金属的颗粒物（PM）的吸入可能会对受影响社区的心血管和肺部疾病造成未被认识的风险。空气中PM中的金属与不良心血管和肺部结局，特别是慢性炎症性血管疾病之间存在密切联系。然而，许多毒理学研究都集中在可溶形式的金属上，这与航运业中燃烧残油更为相关。在美国西南部有许多地方，采矿废物导致金属混合物严重污染土壤，导致高水平的铀（U），铜（Cu），钒（V），镍（Ni）和砷（As）等。我们将评估从有混合金属污染史的社区获得的吸入颗粒物的直接和间接致动脉粥样硬化影响。该工作模型涉及肺中导致诱导血管内皮炎症反应的次级循环产物的复杂相互作用。免疫调节受体，如CD 36，TLR 4和氧化低密度脂蛋白（LOX-1）的凝集素样受体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知之甚少。我们假设，肺部暴露于富含金属的PM从矿山废物污染的部落地区将产生循环因子，如氧化低密度脂蛋白，这反过来又激活炎症反应和功能障碍的内皮细胞，依赖于免疫调节受体。以下目标将以机械和翻译的方式解决这个假设。在第一个目标中，我们将比较从矿区吸入的粉尘样品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功能障碍中的作用，这些功能障碍源于暴露于富含金属的PM。我们将在体内和体外选择性拮抗oxLDL/LOX-1通路，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暴露，以检查与内皮损伤和血清炎症潜力的循环标志物的相关性。我们将模拟风吹粉尘暴露，并将炎症/内皮损伤标志物（oxLDL，可溶性ICAM和VCAM，内皮素-1）和纳瓦霍族252名成员的血清生物活性的结果联系起来。表征污染场地可修复PM的健康影响将提供与危害识别和生物相容性相关的重要信息，以支持风险管理和修复策略的优先级。

 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.