Investigating Recruited Lung Macrophage Programming and Turnover in Self-Limited Versus Prolonged Lung Inflammation

研究自限性与长期肺部炎症中招募的肺巨噬细胞编程和周转

• 批准号: 10749322
• 负责人: Emily Mertens King
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749322
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Affect; Alveolar Macrophages; Apoptotic; Automobile Driving; Bacterial Pneumonia; Bleomycin; Bone Marrow; Cells; Clinical; Data; Data Analyses; Data Set; Deoxyuridine; Detection; Disease; Embryonic Development; Epithelium; Exhibits; Fibrosis; Flow Cytometry; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Heterogeneity; Homeostasis; Hypoxemia; In Situ; Inflammation; Inflammatory; Injury; Intervention; Kinetics; Knowledge; Label; Laboratories; Lipopolysaccharides; Lung; Macrophage; Mechanical ventilation; Modeling; Morbidity - disease rate; Mus; Neutrophil Infiltration; Pathogenesis; Patients; Physiologic pulse; Play; Population; Proliferating; Pulmonary Fibrosis; Pulmonary Inflammation; Reporter; Role; Sepsis; Structure of parenchyma of lung; Tamoxifen; Testing; Time; Tissues; Viral Pneumonia; Work; chemokine; cytokine; cytotoxic; experience; improved; indium-bleomycin; insight; interstitial; lung injury; migration; monocyte; mortality; mouse model; non cardiogenic pulmonary edema; outcome disparities; recruit; single-cell RNA sequencing; timeline; tissue repair

PROJECT SUMMARY The acute respiratory distress syndrome (ARDS) is characterized by severe lung inflammation and carries a mortality of 30-40%. Some patients recover quickly while others improve slowly and often develop lung fibrosis. The factors that drive these disparate outcomes are unclear. Pulmonary macrophages play key roles in the pathogenesis of ARDS by releasing inflammatory cytokines, recruiting neutrophils, and releasing cytotoxic and apoptotic factors which damage the lung epithelium. I hypothesize that inflammatory programming of pulmonary macrophages and continuous recruitment of monocytes with inflammatory programming into the lung drive prolonged inflammation and transient fibrosis in acute lung injury. Aim 1 of this proposal will use an existing single-cell RNA sequencing (scRNAseq) dataset generated by the Janssen laboratory to test the hypothesis that specific recruited monocyte-derived macrophage subsets from a mouse model of prolonged inflammation will exhibit transcription profiles consistent with perpetuating inflammation and fibrosis. This transcription profile would include expression of pro-inflammatory cytokines, chemokines, and cytotoxic factors. The transcriptional programming of recruited macrophages in a prolonged inflammation model will be compared to recruited macrophages from a model of self-limited inflammation. Aim 2 will use a compartment and lineage tracing mouse model I have optimized to test the hypothesis that prolonged lung inflammation is characterized by continuous recruitment of monocytes into the airspace and pulmonary interstitium that mature into pro-inflammatory macrophages, with little proliferation in situ whereas self-limited inflammation is characterized by an early, single wave of recruitment. Understanding the transcriptional profiles of recruited macrophage populations will provide insight into the pathophysiology of limited versus prolonged lung inflammation. Defining the kinetics of monocyte recruitment to the airspace and interstitium in limited versus prolonged inflammation will inform both the pathophysiology of slowly resolving lung inflammation and the timeline for interventions.

项目摘要 急性呼吸窘迫综合征（ARDS）的特征是严重的肺部炎症， 死亡率为30- 40%。一些患者恢复迅速，而另一些患者改善缓慢，并经常发展为肺纤维化。 导致这些不同结果的因素尚不清楚。肺巨噬细胞在肿瘤的发生发展中起着关键作用。 通过释放炎性细胞因子、募集中性粒细胞和释放细胞毒性和 细胞凋亡因子损伤肺上皮。我假设肺的炎症性编程 巨噬细胞和单核细胞的持续募集与炎症编程进入肺驱动 急性肺损伤中的长期炎症和短暂纤维化。本提案的目标1将使用现有的 Janssen实验室生成的单细胞RNA测序（scRNAseq）数据集，以检验以下假设： 来自长期炎症小鼠模型的特异性募集的单核细胞衍生的巨噬细胞亚群将 表现出与持续炎症和纤维化一致的转录谱。这个转录谱 包括促炎细胞因子、趋化因子和细胞毒性因子的表达。转录 将在长期炎症模型中募集的巨噬细胞的编程与在长期炎症模型中募集的巨噬细胞的编程进行比较。 巨噬细胞的自限性炎症模型。目标2将使用隔室和谱系追踪小鼠 模型我已经优化，以检验这一假设，即长期的肺部炎症的特点是持续的， 单核细胞募集到空气和肺动脉内膜中，成熟为促炎性细胞， 巨噬细胞，几乎没有原位增殖，而自限性炎症的特征是早期，单一的 招聘浪潮了解募集的巨噬细胞群体的转录谱将提供 了解有限与长期肺部炎症的病理生理学。定义单核细胞的动力学 在有限与长期炎症中，向空域和肺组织的招募将告知 缓慢缓解肺部炎症的病理生理学和干预的时间轴。