Monocyte-derived alveolar macrophage drives inflammatory response to lung ozone exposure

单核细胞来源的肺泡巨噬细胞驱动对肺臭氧暴露的炎症反应

• 批准号: 10689120
• 负责人: Alexander Misharin
• 金额: $ 60.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689120
• 关键词: 2019-nCoV; Acute; Address; Alveolar; Alveolar Macrophages; COVID-19 pandemic; COVID-19 pneumonia; Cells; Chronic lung disease; Data; Environmental Exposure; Equilibrium; Exposure to; Genomics; Growth Factor; Homeostasis; Human; Immune; Immune Targeting; Individual; Inflammation; Inflammatory Response; Influenza; Laboratories; Link; Lung; Macrophage; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Morbidity - disease rate; Mus; Ozone; Patients; Performance; Phenotype; Physiological; Pneumonia; Population; Populations at Risk; Predisposition; Public Health; Publishing; Pulmonary Fibrosis; Pulmonary Inflammation; Receptor Signaling; Reporting; Resolution; Role; Sampling; Seminal; Severities; Signal Transduction; Stromal Cells; System; Techniques; Testing; Tissue Expansion; Tissues; Viral; Viral Respiratory Tract Infection; Virus Diseases; Work; autocrine; cell type; human subject; immunological intervention; influenzavirus; lung injury; monocyte; mortality; mouse model; novel; novel therapeutic intervention; ozone exposure; pathogen exposure; post SARS-CoV-2 infection; pulmonary function; recruit; respiratory; respiratory health; response; seasonal influenza; single cell analysis; transcriptomics

Abstract: Morbidity and mortality associated with ozone (O3) exposures are a substantial public health concern. Unlike other environmental exposures, O3-related morbidity and mortality, is largely linked to respiratory causes and associated with pre-existing respiratory conditions. However, specific mechanisms underlying this phenomenon are poorly understood. Understanding how prior lung injury drives susceptibility to subsequent O3 exposure is particularly important in the context on viral lung injury, such as pneumonia caused by seasonal influenza virus or SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic. Our overall hypothesis is that this is driven by distinct alveolar macrophage (AMØ) subsets. During the past decade, work from several groups, including ours, has demonstrated that long-living, self-maintaining, tissue-resident AMØ are the dominant immune cell type in normal mouse and human lung. Tissue-resident AMØ are essential to lung homeostasis and direct responses to pathogens and environmental exposures, including O3. We have previously reported that murine O3 exposure expands tissue-resident AMØ, and their loss exacerbates O3-induced lung injury. Conversely, monocyte-derived AMØ, recruited during lung injury (e.g. viral infection), augment inflammation. Our group previously showed that monocyte-derived AMØ recruited after lung injury persist in the lung via autocrine M-CSF/M-CSF receptor (M-CSF-R), maintain an activated phenotype, and drive chronic lung diseases. Extending this to humans, we demonstrate that the abundance and activation state of monocyte-derived AMØs negatively correlate with pulmonary function in patients with early pulmonary fibrosis. Cumulatively, our published and preliminary data support that distinct AMØ subsets direct the balance between ongoing inflammation and its resolution and suggest that AMØ composition, particularly the baseline presence and activation of monocyte-derived AMØ, prior to exposure can enhance severity and persistence of O3-induced lung injury. This baseline condition is particularly important as respiratory viral infections, including influenza and SARS-CoV2, induce the recruitment of monocyte-derived AMØs. Leveraging mechanistic mouse models, state- of-the-art lineage-tracing systems, single-cell genomics, and serial sampling in controlled human O3 exposures, we will test the hypothesis that the abundance and activation state of monocyte-derived AMØs drive O3- induced lung inflammatory responses via autocrine M-CSF/M-CSF-R signaling. Our specific aims are: Aim 1: To determine the role of autocrine monocyte-derived alveolar macrophage M-CSF/M-CSF-R signaling in maintaining lung inflammation in mouse models of O3-exposure. Aim 2: To determine whether the abundance and activation status of monocyte-derived AMØ predicts lung physiological and inflammatory responses in controlled acute O3 exposures in normal human subjects and in individuals with prior SARS-CoV2 infection. These results would support a novel translational paradigm with important public health implications, and identify a novel therapeutic strategy to revert the adverse public health effects of O3 exposure.

抽象的： 与臭氧（O3）暴露相关的发病率和死亡率是一个实质性的公共卫生问题。与众不同 其他环境暴露，与O3相关的发病率和死亡率，在很大程度上与呼吸系统有关 与现有的呼吸系统疾病有关。但是，这种现象的基本机制 知之甚少。了解先前的肺损伤如何使后续O3暴露的敏感性是 在病毒肺损伤的背景下，例如季节性影响力引起的肺炎尤其重要 或SARS-COV-2，即正在进行的Covid-19-19大流行的致病药物。我们的总体假设是 由独特的肺泡巨噬细胞（AMø）子集驱动。在过去的十年中，来自多个小组的工作， 包括我们在内的，已经证明了悠久的，自我维护的组织居民Amø是主要的 正常小鼠和人肺中的免疫细胞类型。组织居民Amø对于肺稳态至关重要 对病原体和环境暴露的直接反应，包括O3。我们以前已经报道了 鼠O3暴露会扩大组织居民的Amø，其损失加剧了O3诱导的肺损伤。 相反，单核细胞衍生的Amø，在肺部受伤期间招募（例如病毒感染），增强注射。我们的 先前的小组表明，单核细胞衍生的Amø在肺损伤通过自分泌持续存在 M-CSF/M-CSF受体（M-CSF-R），保持活化的表型，并驱动慢性肺部疾病。 将其扩展到人类，我们证明了单核细胞衍生的Amøs的抽象和激活状态 早期肺纤维化患者中与肺功能负相关。累积，我们的 已发表和初步数据支持，不同的Amø子集指导正在进行的平衡 炎症及其分辨率，并表明Amø成分，尤其是基线的存在和 在暴露之前激活单核细胞衍生的Amø，可以增强O3诱导的肺的严重程度和持久性 受伤。这种基线条件特别重要，因为呼吸道病毒感染，包括影响力和 SARS-COV2，诱导单核细胞来源的Amøs招募。利用机械小鼠模型，状态 - 在受控的人O3暴露中，ART谱系跟踪系统，单细胞基因组学和串行采样， 我们将检验以下假设：单核细胞衍生的Amøs驱动O3-的抽象和激活状态 通过自分泌M-CSF/M-CSF-R信号传导引起的肺炎症反应。我们的具体目标是：目标 1：确定自分泌单核细胞衍生的肺泡巨噬细胞M-CSF/M-CSF-R信号在 在O3暴露的小鼠模型中保持肺注射。目标2：确定是否丰富 和单核细胞衍生的Amø预测的激活状态肺生理和炎症反应 正常人受试者和先前SARS-COV2感染的个体中受控的急性O3暴露。 这些结果将支持具有重要公共卫生影响的新型翻译范式，并确定 一种新型的热策略，旨在恢复O3暴露的不利公共卫生影响。