Inhaled Mine-Site Derived Metal Particulate Matter Drives Pulmonary and Systemic Immune Dysregulation

吸入矿场产生的金属颗粒物会导致肺部和全身免疫失调

• 批准号: 10353205
• 负责人: Alicia M. Bolt
• 金额: $ 23.44万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353205
• 关键词: Address; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Biological Monitoring; Bone Marrow; Cells; Chronic; Chronic lung disease; Coculture Techniques; Collaborations; Communities; Data; Development; Disease; Dust; Environmental Exposure; Epithelial Cells; Exhalation; Exposure to; Geography; Goals; Health; Human; Hyperactivity; Image; Immune; Immune System Diseases; Immunologic Markers; Immunologics; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inhalation; Inhalation Exposure; Interstitial Lung Diseases; Iron; Lead; Link; Lung; Machine Learning; Measures; Mediating; Metal exposure; Metals; Minerals; Mining; Modeling; Mus; Navajo; New Mexico; Outcome; Oxidative Stress; Particulate; Particulate Matter; Pathology; Pathway interactions; Population; Postdoctoral Fellow; Pueblo Race; Pulmonary Inflammation; Research; Respiration Disorders; Risk; Role; Route; Sampling; Silicon Dioxide; Silicosis; Site; Southwestern United States; Superfund; Toxic effect; Translating; Universities; Uranium; Vanadium; Work; base; bone; cohort; community living; cytokine; exposed human population; extracellular; imaging platform; immunoregulation; in vitro Model; inhibitor; innovation; insight; lung development; lung injury; macrophage; member; metal complex; metal poisoning; mouse model; nasopharyngeal swab; neutrophil; novel; pre-clinical; programs; research study; response; systemic autoimmunity; tool; tribal community; tribal lands

Project Summary/Abstract Inhalation of mine site dust is a relevant route of human exposure to metal mixtures that poses a significant health concern for tribal communities living near abandoned uranium and hard rock mine sites in the four- corners region of the Southwestern United States. The University of New Mexico's Metals Exposure and Toxicity Assessment on Tribal Land in the Southwest (UNM METALS) team has demonstrated that exposure of individuals in the Navajo Nation to metal mixtures is associated with biomarkers of immune dysregulation and living in close proximity to abandoned uranium mines correlates with levels of anti-nuclear autoantibodies. This region is also a geographic epicenter for interstitial lung disease, silicosis and other chronic respiratory disorders, which are linked to environmental exposures and systemic autoimmunity. It is currently not known how inhaled metal-rich particulates drive extrapulmonary immunological dysregulation. In addition, the contribution of different individual metals (e.g., uranium, vanadium, and iron) in driving these immune-mediated changes has yet to be clearly defined. BioProject – Lung (BP Lung) focuses on investigating mechanisms of metal-mediated immune dysregulation both locally in the lungs, as well as systemically following inhalation exposure to metal-rich particulates. Thus, our main objective is to determine how these changes contribute to pulmonary injury and autoimmune development. Because metals accumulate in bone and we have evidence that inflammatory changes in the bone marrow niche mirror pulmonary responses following particulate exposure, a second goal is to investigate crosstalk between the bone marrow niche and the lungs contributing to metal particulate-mediated immune dysfunction. Our central hypothesis is that uranium and uranium-rich particulate mixtures drive pulmonary and systemic immune dysregulation and autoimmunity through hyperactive NETosis, in part by priming neutrophils for NETosis in the bone marrow niche. In Aim 1, we will utilize a novel high content imaging, machine learning-based single cell platform to investigate how individual metals alone or in combination with other metals and minerals contribute to oxidative stress, inflammation, and NETosis using human, in vitro models. In Aim 2, we will use an autoimmune prone mouse model to determine the role of neutrophils and NETosis in the development of airborne metal-mediated lung and systemic immune dysregulation and autoimmune development using several established NETosis inhibitors. In Aim 3, we will translate our mechanistic findings from Aims 1 and 2 to investigate associations between airborne metal exposure and airway inflammatory mediators in individuals from Laguna Pueblo partnering community in collaboration with BP Comm and CEC. This work is innovative and significant because it utilizes state-of-the art tools to provide detailed understanding of the effect of neutrophils and NETosis as mechanistic targets and driver of systemic immune dysregulation following metal particulate exposure and how crosstalk between the bone marrow niche and the lungs contribute to these pathologies.

项目摘要/摘要 吸入矿场粉尘是人类接触金属混合物的一种相关途径，对人类构成了显著的 居住在四个废弃的铀矿和硬岩矿场附近的部落社区的健康问题- 美国西南部的角落地区。新墨西哥大学的金属暴露和 对西南部落土地的毒性评估(UNM Metals)小组表明，暴露于 纳瓦霍民族的个体对金属混合物的反应与免疫失调的生物标志物有关 居住在离废弃铀矿很近的地方，与抗核自身抗体水平相关。 该地区也是间质性肺病、矽肺和其他慢性呼吸道疾病的地理震中。 与环境暴露和全身性自身免疫有关的疾病。目前尚不清楚 吸入富含金属的颗粒物如何导致肺外免疫失调。此外， 不同金属(如铀、钒和铁)在免疫介导的这些反应中的作用 变化还有待明确界定。生物项目-肺(BP肺脏)专注于研究 吸入后局部和全身的金属介导的免疫失调 暴露在富含金属的颗粒物中。因此，我们的主要目标是确定这些变化如何有助于 肺损伤和自身免疫发育。因为金属会积聚在骨头里而我们有证据 骨髓龛中的炎症变化反映了颗粒物引起的肺反应 暴露，第二个目标是调查骨髓壁龛和肺部之间的串扰。 到金属微粒介导的免疫功能障碍。我们的中心假设是铀和富含铀的 颗粒物混合物通过以下途径驱动肺和全身免疫失调和自身免疫 过度活跃的网织红细胞增多症，部分是通过启动骨髓中中性粒细胞的网织红细胞增多症来实现的。在目标1中，我们将 利用新的高内容成像、基于机器学习的单细胞平台来调查个体 金属本身或与其他金属和矿物质结合会导致氧化应激、炎症和 使用人类的网虫病，体外模型。在目标2中，我们将使用倾向于自身免疫的小鼠模型来确定 中性粒细胞和网织红细胞在气载金属介导的肺和系统免疫中的作用 使用几种已确定的NETase抑制剂的调节失调和自身免疫发展。在《目标3》中，我们将 翻译我们来自AIMS 1和2的机械发现，以研究空气中金属之间的关联 年拉古纳普韦布洛合伙社区个人暴露与呼吸道炎症介质 与BP Comm和CEC合作。这项工作具有创新性和重要意义，因为它利用了最新的 ART工具提供详细了解中性粒细胞和网织红细胞增多症作为机械性靶点的作用和 金属微粒暴露后全身免疫失调的驱动因素以及 骨髓龛和肺是导致这些病理改变的原因。