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重大的公共卫生问题。 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原因和 然而，这种现象背后的具体机制。 人们对先前的肺损伤如何导致对随后的氧气暴露的易感性知之甚少。 对于病毒性肺损伤（例如季节性流感病毒引起的肺炎）尤其重要 或 SARS-CoV-2，当前 COVID-19 大流行的病原体。我们的总体假设是，这就是。 由不同的肺泡巨噬细胞（AMØ）亚群驱动在过去的十年中，来自多个小组的工作， 包括我们在内，已经证明长寿命、自我维持、组织驻留的 AMØ 是主要的 正常小鼠和人肺中组织驻留的 AMØ 免疫细胞类型对于肺稳态和免疫功能至关重要。 对病原体和环境暴露（包括 O3）的直接反应我们之前曾报道过。 小鼠 O3 暴露会扩大组织驻留 AMØ，其损失会加剧 O3 引起的肺损伤。 离线、单核细胞衍生的 AMØ，在肺损伤（例如病毒感染）期间招募，加剧炎症。 研究小组之前表明，肺损伤后募集的单核细胞来源的 AMØ 通过自分泌持续存在于肺部 M-CSF/M-CSF 受体 (M-CSF-R) 维持激活的表型，并导致慢性肺部疾病。 将其扩展到人类，我们证明单核细胞衍生的 AMØ 的丰度和激活状态 累积而言，与早期肺纤维化患者的肺功能呈负相关。 已发布的和初步的数据支持不同的 AMØ 子集指导正在进行的之间的平衡 炎症及其消退，并表明 AMØ 组成，特别是基线存在和 在暴露之前激活单核细胞衍生的 AMØ 可以增强 O3 诱导的肺损伤的严重程度和持久性 这种基线状况对于呼吸道病毒感染（包括流感和流感）尤为重要。 SARS-CoV2，利用机械小鼠模型诱导单核细胞衍生的 AMØ 的募集，状态- 最先进的谱系追踪系统、单细胞基因组学和受控人类 O3 暴露中的连续采样， 我们将检验单核细胞来源的 AMØ 的丰度和激活状态驱动 O3- 的假设 通过自分泌 M-CSF/M-CSF-R 信号传导诱导肺部炎症反应 我们的具体目标是： 1: 确定自分泌单核细胞来源的肺泡巨噬细胞 M-CSF/M-CSF-R 信号在 在 O3 暴露的小鼠模型中维持肺部炎症 目标 2：确定丰度是否存在。 单核细胞来源的 AMØ 的激活状态可预测肺生理和炎症反应 控制正常人类受试者和既往感染过 SARS-CoV2 的个体的急性 O3 暴露。 这些结果将支持具有重要公共卫生影响的新型转化范式，并确定 一种新颖的治疗策略，可恢复 O3 暴露对公共健康的不利影响。