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: 10707529
• 负责人: Alicia M. Bolt
• 金额: $ 24.64万
• 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/10707529
• 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; Link; Lung; Machine Learning; Macrophage; Measures; Mediating; Metal exposure; Metals; Minerals; Mining; Modeling; Mus; Navajo; New Mexico; Nuclear; Outcome; Oxidative Stress; Particulate; Particulate Matter; Pathology; Pathway interactions; Physical condensation; Population; 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; bone; cohort; community living; cytokine; exposed human population; extracellular; imaging platform; immunoregulation; in vitro Model; inflammatory marker; inhibitor; innovation; insight; lung development; lung injury; 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 吸入矿场灰尘是人类暴露于金属混合物的相关途径，这显着 居住在四分之一的废弃铀和硬石矿场附近的部落社区的健康关注 - 美国西南部的角落地区。新墨西哥大学的金属暴露和 西南部落土地（UNM金属）团队的毒性评估证明了暴露 纳瓦霍（Navajo）国家的个人与金属混合物有关，与免疫失调的生物标志物有关 与抗核自身抗体水平相关的靠近废弃铀矿的靠近。 该地区也是地理震中，用于间质肺部疾病，硅和其他慢性呼吸道 疾病，与环境暴露和全身自身免疫有关。目前尚不清楚 富含金属的组件如何驱动肺外免疫失调。另外， 不同的单个金属（例如铀，钒和铁）在驱动这些免疫介导的贡献 更改尚未明确定义。 Bioproject - 肺（BP肺）专注于研究机制 金属介导的免疫失调均在肺部局部以及发生事故发生后的局部。 暴露于金属富含的组件。这是我们的主要目标是确定这些变化如何促进 肺损伤和自身免疫发育。因为金属积聚在骨头上，我们有证据 特定后， 暴露，第二个目标是调查骨髓小裂和肺之间的串扰 到金属特定的免疫功能障碍。我们的中心假设是铀和铀丰富 颗粒混合物驱动肺部和全身免疫失调和自身免疫性通过 多活跃的Netosis，部分是通过雷神为骨髓小裂中的脂肪粒细胞引发。在AIM 1中，我们将 利用一种新型的高内容成像，基于机器学习的单细胞平台来研究个人 金属单独或与其他金属和矿物质结合有助于氧化应激，感染和 使用人类，体外模型的Netosis。在AIM 2中，我们将使用自身免疫性俯卧鼠模型来确定 中性粒细胞和Netosis在空气中金属介导的肺和全身免疫的发育中的作用 使用几种已建立的Netosis抑制剂的失调和自身免疫性发育。在AIM 3中，我们将 从目标1和2转换我们的机械结果，以调查空气金属之间的关联 来自Laguna Pueblo合作伙伴社区个人的曝光和气道炎症调解人 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 艺术工具以详细了解中性粒细胞和netosis作​​为机械目标和 金属特定暴露后全身免疫失调的驱动器以及如何在 骨髓小裂和肺有助于这些病理。