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

肺炎是一种常见病，也是导致发病和死亡的常见原因。S.肺炎是最 是社区获得性肺炎的常见原因，也是一个主要的健康问题。了解肺宿主 防御反应，这种生物体和成功的解决炎症和免疫反应， 重要且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的反应中，宿主防御的关键手臂。的分类 亚群是非常热门和有争议的。我们重点讨论了巨噬细胞的分类， 识别三个亚群的表面标志物：肺泡巨噬细胞（AM）、间质巨噬细胞 (IMs)和炎性巨噬细胞（InfM）。我们的初步研究表明，在未受到挑战的肺部， 是存在于气道/肺泡中的唯一可灌洗的巨噬细胞。PBS处理（对照）肺的消化物 结果表明，在肺巨噬细胞总数中，约28%为AM，50%为IM，22%为InfM。基因分析 分离的亚群揭示了每个亚群非常不同的mRNA表达模式，表明 在卫生方面，每个亚群都有独特的职能。在肺炎期间， 亚群发生了巨大的变化最初，肺巨噬细胞的总数增加3-4倍， 反映了AM的数量减少，InFM的数量增加，而IM没有变化。第14天， 数量几乎恢复到健康肺中的数量，但AM现在来自骨髓和肺部 起源.因此，这些亚群是非常动态的，并且很可能具有特定的功能， 在肺炎过程中每个亚群内的变化。此外，这些细胞特异性变化 在数量和功能上很可能受到肺泡微环境的调节， 在感染和免疫反应期间。我们的研究使用肺保护放射线和骨髓 重组产生嵌合小鼠，但不改变肺巨噬细胞亚群。目标 检验肺巨噬细胞亚群各自在以下方面发挥特定和重要作用的总体假设： 细菌性肺炎期间的宿主防御，以期确定新的重要机制 这些过程的基础。目的1确定贩运动力学，包括 肺炎期间的肺巨噬细胞以及这些变化发生的机制。目的2 决定每个巨噬细胞亚群的功能。目的3确定牙槽骨的作用 微环境对巨噬细胞亚群的动力学和功能的影响。这些研究测试了 假设特定亚群的运输和功能将由实质ICAM-1调节， 通过CX 3CL 1/R1（fractalkine）轴，以及通过Nrf 2介导的抗氧化损伤的细胞保护。

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.