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.

项目摘要/摘要环境吸入暴露是固有的混合（气体和颗粒），但环境法规仍基于单一有毒物质暴露。在标准化中开发和研究共曝光方案而受控的时尚将使对环境暴露如何导致的机械理解有更好的理解不利的结果。共同曝光的影响很少，尤其是在易感人群中急性肺损伤的人（ALI）。在没有关于环境共同曝光的知识的情况下，它将减轻环境疾病的负担并发展有效，也很难（即使不是不可能）要非常困难作为保护公共卫生的现实暴露限制。该提议的目的是阐明炭黑（CB；超细颗粒的碳核的替代物）和臭氧（O3）吸入共曝光 - ALI后，诱导的肺损伤和小鼠上皮再生的调节。我们将进一步机械表征线粒体核苷酸结合寡聚域的作用，类似于受体X1（NLRX1）在这些回应。我们假设对CB的共同暴露和O3协同增加了肺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营养不良，导致重新编程肺泡祖细胞（AT2）细胞，以改变肺泡再生。我们的研究计划专门结合艺术水吸入共同曝光，独特的鼠标模型和3-D Organoid 培养以阐明健康和受伤肺中共曝光诱导肺损伤的机制（易感模型）。我们的初步研究表明O3和CB吸入共曝光协同加剧肺损伤，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微生物营养不良。老鼠缺乏NLRX1在共曝光后表现出严重加剧的炎症反应。牙槽2（AT2）细胞（肺泡祖细胞）显示出明显的细胞凋亡，线粒体损伤和形成的能力受损共曝光后3-D肺泡器官。博来霉素（BLM）诱导的肺上皮损伤显着增加，而上皮增殖在共曝光后受到损害。我们的具体目的是1）确定共同暴露后肺部炎症的协同生物学活性和机制，2）确定如何确定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的结果和3）在与OR共同暴露期间表征微生物组 - 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营养不良），环境暴露会影响ALI 结果。这些发现将有助于理解共同曝光对不良肺影响的影响并制定预防性和治疗性的努力，以改善空气污染的健康影响。