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.

摘要： 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。不像 其他环境暴露，如与臭氧有关的发病率和死亡率，在很大程度上与呼吸道原因和 与先前存在的呼吸系统疾病有关。然而，这种现象背后的具体机制 人们对此了解甚少。了解先前的肺损伤如何导致对随后的臭氧暴露的易感性 在病毒性肺损伤方面尤其重要，例如季节性流感病毒引起的肺炎 或者SARS-CoV-2，正在进行的新冠肺炎大流行的病原体。我们的总体假设是，这是 由不同的肺泡巨噬细胞(AM？)亚群驱动。在过去的十年里，几个组织的工作， 包括我们的在内，已经证明了长寿命、自我维持、组织驻留的AM？是主要的 正常小鼠和人肺的免疫细胞类型。驻留在组织中的AM？对肺内稳态和 对病原体和环境暴露的直接反应，包括臭氧。我们之前已经报道过， 小鼠暴露在臭氧中会扩大组织中的AM？，它们的丢失加剧了臭氧所致的肺损伤。 相反，在肺损伤(如病毒感染)期间招募的单核细胞来源的AM？会加剧炎症。我们的 研究小组先前的研究表明，肺损伤后单核细胞来源的AM？通过自分泌在肺内持续存在 M-CSF/M-CSF受体(M-CSF-R)，维持活化表型，推动慢性肺部疾病。 将其推广到人类，我们证明了单核细胞来源的AM？S的丰度和激活状态 早期肺纤维化患者的肺功能与肺功能呈负相关。累积起来，我们的 已公布的和初步的数据支持不同的AM？子集指导正在进行的 炎症及其消退，并提示AM？成分，特别是基线存在和 暴露前激活单核细胞来源的AM？可增强臭氧所致肺损伤的严重性和持久性 受伤。这一基线情况尤其重要，因为呼吸道病毒感染，包括流感和 SARS-CoV2，诱导单核细胞来源的AM？S募集。利用机械小鼠模型，状态- 最先进的血统追踪系统、单细胞基因组学和受控人类臭氧暴露的连续采样， 我们将检验这样一种假设，即单核细胞来源的AM？S的丰度和激活状态驱动O_3- 通过自分泌M-CSF/M-CSF-R信号诱导肺炎性反应。我们的具体目标是：目标 1.确定自分泌的单核细胞来源的肺泡巨噬细胞M-CSF/M-CSF-R信号转导通路在肺损伤中的作用 维持臭氧暴露小鼠模型的肺部炎症。目标2：确定丰度是否 单核细胞来源的AM？的激活状态可预测肺的生理和炎症反应 正常人和既往感染SARS-CoV2的人的受控急性臭氧暴露。 这些结果将支持一种具有重要公共卫生影响的新的翻译范式，并确定 一种新的治疗策略，以逆转臭氧暴露对公共健康的不利影响。