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

描述（由申请人提供）：心血管和代谢性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辅助心血管疾病（CVD）因素的作用。在新墨西哥州和纳瓦霍族，存在着许多被遗弃和未修复的矿区，并继续污染着土地、水和空气。从采矿废物中吸入富含金属的颗粒物（PM）可能对受影响社区的心血管和肺部疾病造成未被认识到的风险。空气中PM中的金属与心血管和肺部不良后果，特别是慢性炎症性血管疾病之间存在密切联系。然而，大部分毒理学研究都集中在可溶形式的金属上，这与航运业燃烧残油更相关。在美国西南部有许多地方，采矿废料导致严重的土壤金属混合物污染，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。工作模型涉及肺部复杂的相互作用，导致二次循环产物，诱导血管内皮炎症反应。免疫调节受体，如CD36、TLR4和氧化低密度脂蛋白（LOX-1）的卵磷脂样受体介导血管对空气污染中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作用尚不清楚。我们假设，肺部暴露于来自矿山废物污染的部落地区的富含金属的PM将产生循环因子，如氧化LDL，进而激活炎症反应和内皮细胞功能障碍，依赖于免疫调节受体。以下的目的将以机械和翻译的方式解决这一假设。在第一个目标中，我们将比较从矿区吸入的粉尘样本在驱动全身血管毒性和血清炎症潜能方面的效力。在第二个目标中，我们将研究oxLDL和免疫调节受体在驱动暴露于富含金属的PM的内皮细胞激活和功能障碍中的作用。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建立顺风暴露模型，以检查与内皮损伤和血清炎症潜力循环标志物的关联。我们将模拟风尘暴露，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结果联系起来。表征来自受污染场地的可修复颗粒物对健康的影响，将提供与危害识别和生物合理性相关的重要信息，以支持确定风险管理和补救战略的优先次序。

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.