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Impact of particle and ozone inhalation co-exposure on alveolar epithelial regeneration

颗粒物和臭氧吸入共同暴露对肺泡上皮再生的影响

基本信息

批准号：
10153788
负责人：
Salik Hussain
金额：
$ 59.1万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10153788
关键词：
3-Dimensional Acute Acute Lung Injury Aerosols Air Pollution Alveolar Animal Model Apoptosis Attention Automobile Driving Binding Biological Bleomycin Carbon Carbon Black Cells Characteristics Clinical Dependence Development Disease Dose Drops Engineering Environmental Exposure Environmental Impact Environmental Pollution Environmental Risk Factor Epithelial Exhibits Exposure to Free Radicals Functional disorder Gases Gene Expression General Population Genetic Genetically Modified Animals Goals Health Impairment Incidence Individual Inflammation Inflammatory Inflammatory Response Inhalation Inhalation Exposure Injury Knock-out Knowledge Life Lung Lung Inflammation Lung diseases Mediating Mitochondria Mitogen-Activated Protein Kinase Inhibitor Modeling Morbidity - disease rate Mus Natural regeneration Nucleotides Organoids Outcome Oxidants Oxidative Phosphorylation Oxidative Stress Oxides Ozone Particulate Pathogenesis Pathology Pathway interactions Permeability Phase Population Predisposition Preventive Production Public Health Regulation Reporting Research Respiration Role Standardization Surface Syndrome Therapeutic Time Toxic effect Toxicant exposure Ultrafine World Health Organization adverse outcome alveolar epithelium base dysbiosis epithelial injury epithelium regeneration gut microbiome gut-lung axis injury and repair lung injury lung microbiome lung regeneration microbial microbiome mitochondrial dysfunction mortality mouse model novel particle particulate pollutant prevent progenitor programs protein expression pulmonary function pulmonary function decline receptor response stem cells therapeutic target tropospheric ozone ultrafine particle

项目摘要

PROJECT SUMMARY/ABSTRACT Environmental inhalation exposures are inherently mixed (gases and particles), yet environmental regulations are still based on single toxicant exposures. Developing and studying the co-exposure scenario in a standardized and controlled fashion will enable a better mechanistic understanding of how environmental exposures result in adverse outcomes. The impact of co-exposures is poorly studied, especially in susceptible populations such as individuals with acute lung injury (ALI). In the absence of such knowledge on environmental co-exposures, it will be very difficult, if not impossible, to reduce the burden of environmental disease and develop effective as well as realistic exposure limits to safeguard public health. The goal of this proposal is to elucidate mechanisms of carbon black (CB; surrogate of the carbon core of ultrafine particles) and ozone (O3) inhalation co-exposure- induced lung injury and modulation of epithelial regeneration in mice following ALI. We will further mechanistically characterize the role of mitochondrial nucleotide-binding oligomerization domain-like Receptor X1 (NLRX1) in these responses. We hypothesize that co-exposure to CB and O3 synergistically increases pulmonary damage by oxidizing the particle surfaces, causing NLRX1 mediated mitochondrial dysfunction and microbial dysbiosis, leading to reprogramming of the alveolar progenitor (AT2) cells for altered alveolar regeneration. Our research plan exclusively combines state of the art inhalation co-exposures, unique mouse models, and 3-D organoid cultures to elucidate the mechanisms of co-exposure induced pulmonary damage in healthy and injured lungs (a susceptibility model). Our preliminary studies demonstrate that O3 and CB inhalation co-exposures synergistically exacerbates lung injury, oxidative stress, inflammation, lung function decline, lung permeability, mitochondrial oxidative phosphorylation, and lung microbial dysbiosis compared to individual exposures. Mice lacking NLRX1 exhibit significantly aggravated inflammatory response after co-exposure. Alveolar type 2 (AT2) cells (alveolar progenitor cells) show significant apoptosis, mitochondrial damage, and impaired ability to form 3-D alveolar organoids after co-exposure. Bleomycin (BLM)-induced lung epithelial injury is significantly increased, while epithelial proliferation is impaired after co-exposure. Our specific aims are 1) to determine synergistic biological activity and mechanisms of lung inflammation after co-exposure, 2) to identify how the altered mechanisms of alveolar injury and alveolar progenitor cell dysfunction contribute to progression and outcome of ALI, and 3) to characterize microbiome-alveolar progenitor cell cross-talk during co-exposure with or without ALI. These studies will delineate genetic (NLRX1) and cellular mechanisms (alveolar progenitor mitochondrial dysfunction and microbial dysbiosis) through which environmental exposures impact ALI outcomes. These findings will be helpful in understanding the impact of co-exposures on adverse lung effects and developing preventive and therapeutic efforts to ameliorate the health impact of air pollution.

项目概要/摘要环境吸入暴露本质上是混合的（气体和颗粒），但环境法规仍然基于单一毒物暴露。以标准化方式开发和研究共同曝光场景受控的时尚将使我们能够更好地理解环境暴露如何导致不良后果。共同暴露的影响研究很少，特别是在易感人群中，例如患有急性肺损伤（ALI）的人。如果缺乏有关环境共同暴露的知识，它将减轻环境疾病的负担并有效发展是非常困难的，甚至是不可能的作为保护公众健康的现实暴露限制。该提案的目标是阐明机制炭黑（CB；超细颗粒碳核的替代品）和臭氧（O3）吸入共同暴露- 诱导 ALI 后小鼠的肺损伤和上皮再生的调节。我们将进一步机械化表征线粒体核苷酸结合寡聚化结构域样受体 X1 (NLRX1) 在这些回应。我们假设同时接触 CB 和 O3 会协同增加肺部损伤通过氧化颗粒表面，导致 NLRX1 介导的线粒体功能障碍和微生物失调，导致肺泡祖细胞（AT2）重新编程以改变肺泡再生。我们的研究该计划独家结合了最先进的吸入联合曝光、独特的小鼠模型和 3D 类器官培养物阐明健康和受伤肺部共同暴露引起肺损伤的机制（敏感性模型）。我们的初步研究表明，O3 和 CB 吸入同时暴露协同加剧肺损伤、氧化应激、炎症、肺功能下降、肺通透性、与个体暴露相比，线粒体氧化磷酸化和肺部微生物失调。小鼠缺乏 NLRX1 的小鼠在共同暴露后表现出明显加剧的炎症反应。 2 型肺泡 (AT2) 细胞（肺泡祖细胞）表现出明显的凋亡、线粒体损伤和形成能力受损共同暴露后的 3-D 肺泡类器官。博来霉素（BLM）引起的肺上皮损伤显着增加，而共同暴露后上皮增殖受损。我们的具体目标是 1) 确定共同暴露后肺部炎症的协同生物活性和机制，2）确定如何肺泡损伤和肺泡祖细胞功能障碍的机制改变有助于进展和 ALI 的结果，以及 3) 表征与或共同暴露期间的微生物组-肺泡祖细胞串扰没有阿里。这些研究将描述遗传（NLRX1）和细胞机制（肺泡祖细胞）线粒体功能障碍和微生物失调），环境暴露通过这些因素影响 ALI 结果。这些发现将有助于了解共同暴露对肺部不良影响的影响制定预防和治疗措施以改善空气污染对健康的影响。