Trafficking and function of macrophage subpopulations within the lung microenvironment during pneumonia
Trafficking and function of macrophage subpopulations within the lung microenvironment during pneumonia
批准号:
10320840
负责人:
Claire M Doerschuk
金额:
$58.58万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-01-01 至 2024-12-31
关键词:
AddressAdhesionsAffectAgeAlveolarAlveolar Cell Type IAlveolar MacrophagesAlveolusApoptosisBackBacteriaBacterial PneumoniaBone MarrowBone Marrow CellsBronchiolesCD11 AntigensCD11a AntigenCX3CL1 geneCategoriesCell CountCell physiologyCellsChestClassificationComplexCytoprotectionDataDiseaseEnvironmentEquilibriumFractalkineGene ClusterGene ExpressionGenesHealthHealth StatusHost DefenseITGAM geneITGB2 geneImmune responseInfectionInflammatoryInflammatory ResponseInjuryIntercellular adhesion molecule 1KineticsLeadLeukocytesLungMacrophage-1 AntigenMeasurementMediatingMessenger RNAMethodsMorbidity - disease rateMusNecrosisOrganismOxidantsOxidative StressPathway AnalysisPatternPersonsPhagocytesPlayPneumoniaPopulationProcessProductionProliferatingPublic HealthRadiationResearchResolutionRoleSideSternumStreptococcus pneumoniaeSurfaceTestingTherapeuticType II Epithelial Receptor CellVertebral columnWhole-Body IrradiationWorkarmbasecell typecommunity acquired pneumoniacostexpectationinterstitialintravenous injectionirradiationlung repairmRNA Expressionmacrophagemonocytemortalityneutrophilnovelnovel therapeutic interventionpathogenreconstitutionrecruitresponsetraffickingtranscription factor
中文摘要
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。
英文摘要
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.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
Application of Omics in Lung Disease
-
批准号:8575263
-
项目类别:
-
资助金额:$12.33万
-
财政年份:2013
-
负责人:Claire M Doerschuk
-
依托单位:
Application of Omics in Lung Disease
-
批准号:8722618
-
项目类别:
-
资助金额:$27.0万
-
财政年份:2013
-
负责人:Claire M Doerschuk
-
依托单位:
Project 3: Mouse Models of Smoking-related Diseases: What is the Best
-
批准号:8904705
-
项目类别:
-
资助金额:$80.55万
-
财政年份:2013
-
负责人:Claire M Doerschuk
-
依托单位:
Research Training Program in Pulmonary Host Defense, Inflammation and Immunity
-
批准号:7067770
-
项目类别:
-
资助金额:$12.83万
-
财政年份:2006
-
负责人:Claire M Doerschuk
-
依托单位:
Research Training in Heart, Lung, Blood & Sleep Diseases
-
批准号:7213390
-
项目类别:
-
资助金额:$21.85万
-
财政年份:2006
-
负责人:Claire M Doerschuk
-
依托单位:
Research Training in Heart, Lung, Blood & Sleep Diseases
-
批准号:7007764
-
项目类别:
-
资助金额:$20.22万
-
财政年份:2006
-
负责人:Claire M Doerschuk
-
依托单位:
NHLBI Research Opportunities for Minority Students
-
批准号:6945521
-
项目类别:
-
资助金额:$14.24万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
Rac2 in Pulmonary Microvascular Endothelial Cells
-
批准号:7016315
-
项目类别:
-
资助金额:$36.86万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
NHLBI Research Opportunities for Minority Students
-
批准号:7092597
-
项目类别:
-
资助金额:$14.24万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
Rac2 in Pulmonary Microvascular Endothelial Cells
-
批准号:6919014
-
项目类别:
-
资助金额:$37.75万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
Rac2 in Pulmonary Microvascular Endothelial Cells
-
批准号:7185141
-
项目类别:
-
资助金额:$35.79万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
NHLBI Research Opportunities for Minority Students
-
批准号:7227479
-
项目类别:
-
资助金额:$14.24万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
Rac2 in Pulmonary Microvascular Endothelial Cells
-
批准号:7367166
-
项目类别:
-
资助金额:$34.96万
-
财政年份:2005
-
负责人:Claire M Doerschuk
-
依托单位:
NEUTROPHIL TRANSMIT THROUGH THE PULMONARY MICROVASCULATURE
-
批准号:6612390
-
项目类别:
-
资助金额:$27.43万
-
财政年份:2002
-
负责人:Claire M Doerschuk
-
依托单位:
NEUTROPHIL TRANSMIT THROUGH THE PULMONARY MICROVASCULATURE
-
批准号:6593849
-
项目类别:
-
资助金额:$27.43万
-
财政年份:2002
-
负责人:Claire M Doerschuk
-
依托单位:
NEUTROPHIL TRANSMIT THROUGH THE PULMONARY MICROVASCULATURE
-
批准号:6109754
-
项目类别:
-
资助金额:$27.43万
-
财政年份:1999
-
负责人:Claire M Doerschuk
-
依托单位:
NEUTROPHIL TRANSMIT THROUGH THE PULMONARY MICROVASCULATURE
-
批准号:6272724
-
项目类别:
-
资助金额:$26.31万
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财政年份:1998
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负责人:Claire M Doerschuk
-
依托单位:
NEUTROPHIL TRANSMIT THROUGH THE PULMONARY MICROVASCULATURE
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批准号:6241854
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项目类别:
-
资助金额:$25.74万
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财政年份:1997
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负责人:Claire M Doerschuk
-
依托单位:
CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG
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批准号:6785268
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项目类别:
-
资助金额:$37.75万
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财政年份:1994
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负责人:Claire M Doerschuk
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依托单位:
CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG
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批准号:2695301
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项目类别:
-
资助金额:$26.42万
-
财政年份:1994
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负责人:Claire M Doerschuk
-
依托单位:
海外基金