Trafficking and function of macrophage subpopulations within the lung microenvironment during pneumonia

肺炎期间肺微环境内巨噬细胞亚群的运输和功能

• 批准号: 10320840
• 负责人: Claire M Doerschuk
• 金额: $ 58.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320840
• 关键词: Address; Adhesions; Affect; Age; Alveolar; Alveolar Cell Type I; Alveolar Macrophages; Alveolus; Apoptosis; Back; Bacteria; Bacterial Pneumonia; Bone Marrow; Bone Marrow Cells; Bronchioles; CD11 Antigens; CD11a Antigen; CX3CL1 gene; Categories; Cell Count; Cell physiology; Cells; Chest; Classification; Complex; Cytoprotection; Data; Disease; Environment; Equilibrium; Fractalkine; Gene Cluster; Gene Expression; Genes; Health; Health Status; Host Defense; ITGAM gene; ITGB2 gene; Immune response; Infection; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Kinetics; Lead; Leukocytes; Lung; Macrophage-1 Antigen; Measurement; Mediating; Messenger RNA; Methods; Morbidity - disease rate; Mus; Necrosis; Organism; Oxidants; Oxidative Stress; Pathway Analysis; Pattern; Persons; Phagocytes; Play; Pneumonia; Population; Process; Production; Proliferating; Public Health; Radiation; Research; Resolution; Role; Side; Sternum; Streptococcus pneumoniae; Surface; Testing; Therapeutic; Type II Epithelial Receptor Cell; Vertebral column; Whole-Body Irradiation; Work; arm; base; cell type; community acquired pneumonia; cost; expectation; interstitial; intravenous injection; irradiation; lung repair; mRNA Expression; macrophage; monocyte; mortality; neutrophil; novel; novel therapeutic intervention; pathogen; reconstitution; recruit; response; trafficking; transcription factor

Pneumonia is a common disease and a frequent cause of morbidity and mortality. S. pneumoniae is the most common cause of community-acquired pneumonia and a major health concern. Understanding lung host defense in response to this organism and successful resolution of inflammatory and immune responses is important and likely to have impact on novel ways to intervene therapeutically. Lung macrophages are a critical arm of host defense in healthy lungs and in response to infection or any injury. The classification of subpopulations is very topical and controversial. We have focused on macrophage categories designated by surface markers that identify three subpopulations; alveolar macrophages (AMs), interstitial macrophages (IMs) and inflammatory macrophages (InfMs). In unchallenged lungs, our preliminary studies show that AMs are the only lavageable macrophage present in the airways/alveoli. Digests of PBS-treated (control) lungs reveal that of total lung macrophages, about 28% are AMs, 50% are IMs, and 22% are InfMs. Gene profiling of isolated subpopulations reveals very distinct patterns of mRNA expression by each subpopulation, suggesting in health, each subpopulation has unique functions. During pneumonia, the percentage and number of each subpopulation changes dramatically. Initially, the total number of lung macrophages increases 3-4-fold, which reflects a decrease in the number of AMs, an increase in InfMs and no change in IMs. By 14 days, the numbers are nearly back to those in healthy lungs, but AMs are now from both bone marrow and lung-resident origins. Thus, these subpopulations are very dynamic and very likely to have specific functions that may change within each subpopulation over the course of a pneumonia. Furthermore, these cell-specific changes in number and function are very likely to be modulated by the alveolar microenvironment, which changes during infection and the immune response. Our studies use lung-protected radiation and bone marrow reconstitution that generates chimeric mice but does not alter the lung macrophage subpopulations. The Aims test the overall hypothesis that subpopulations of lung macrophages each play specific and important roles in host defense during bacterial pneumonia, with the expectation of identifying new and important mechanisms underlying these processes. Aim 1 determines trafficking kinetics, including changes in the subpopulations of lung macrophages during pneumonia and the mechanisms through which these changes occur. Aim 2 determines the function of each macrophage subpopulation. Aim 3 determines the effect of the alveolar microenvironment on the kinetics and function of macrophage subpopulations. These studies test the hypothesis that trafficking and function of particular subpopulations will be modulated by parenchymal ICAM-1, by the CX3CL1/R1 (fractalkine) axis, and by Nrf2-mediated cytoprotection against oxidant damage.

肺炎是一种常见病，也是发病率和死亡率的常见原因。肺炎链球菌是最多的 社区获得性肺炎的共同原因和一个主要的健康问题。了解肺部宿主 对这种有机体的反应以及炎症和免疫反应的成功解决的防御是 这很重要，并可能对治疗干预的新方法产生影响。肺巨噬细胞是一种 在健康的肺部和对感染或任何损伤做出反应时宿主防御的关键手臂。第二部分：分类问题 亚群是非常热门和有争议的。我们专注于巨噬细胞类别，由 识别三个亚群的表面标志物：肺泡巨噬细胞、间质巨噬细胞 (IMS)和炎性巨噬细胞(INFMS)。在未受挑战的肺中，我们的初步研究表明AM 是呼吸道/肺泡中唯一可标记的巨噬细胞。PBS处理(对照)肺的消化 肺巨噬细胞中，AM约占28%，IMS约占50%，InfM约占22%。基因图谱分析 分离的亚群显示了每个亚群非常不同的mRNA表达模式，这表明 在健康方面，每个亚群都有独特的功能。在肺炎期间，每种病毒的百分比和数量 亚群发生了巨大的变化。最初，肺巨噬细胞的总数增加了3-4倍，这 反映AM数量的减少，INFMS的增加，而IMS没有变化。到了14天， 数量几乎回到了健康肺的数量，但AM现在既来自骨髓，也来自肺常驻 起源。因此，这些亚群是非常动态的，很可能具有特定的功能，可以 肺炎期间每个亚群内的变化。此外，这些特定于细胞的变化 在数量和功能上很可能受到肺泡微环境的调节，这种微环境会发生变化 在感染和免疫反应过程中。我们的研究使用肺保护辐射和骨髓 重组产生嵌合小鼠，但不改变肺巨噬细胞亚群。目标 检验总体假设，即肺巨噬细胞亚群各自在 细菌性肺炎期间的宿主防御，期望识别新的和重要的机制 潜藏在这些过程中。目标1确定贩运动力学，包括人口亚群的变化 肺炎期间的肺巨噬细胞以及这些变化发生的机制。目标2 确定每个巨噬细胞亚群的功能。目标3确定肺泡的作用 微环境对巨噬细胞亚群动力学和功能的影响。这些研究测试了 假设特定亚群的贩运和功能将受到实质ICAM-1的调节， 通过CX3CL1/R1(Fractalkine)轴，以及Nrf2介导的细胞保护免受氧化损伤。