Influence of the lung microbiome on macrophage responses to lung damage

肺微生物组对巨噬细胞对肺损伤反应的影响

基本信息

  • 批准号:
    10011536
  • 负责人:
  • 金额:
    $ 1.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-28 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

Abstract Aspiration of gastric acid into the lower respiratory tract can lead to pneumonitis, pneumonia, acute lung injury (ALI), and even the more severe ARDS. We propose that the ability to survive a given disease is determined by two main factors, resistance (the ability to ameliorate the root cause of a disease) and tolerance (the ability to cope with the effects the disease). Many innate immune cell types play roles in tissue repair responses. Macrophages polarize into several subtypes with different functions. The largest categories are known as M1 (important in response to infection) and M2 (important in tissue repair and anti-inflammatory). Our data show that at steady-state aveolar macrophages, the tissue resident macrophages of the lung, are polarized towards the M2 pheonotype. Our preliminary data show that acid aspiration induced ALI has a similar impact as infection, inducing an M1 phenotype. Collectively these data suggest that both severe infection and inflammation alter the programming of macrophages, and decrease their ability to induce the repair phenotype. Recent studies have shown that an individual's intestinal microbiome influences the response to many diseases. However, the impact of the lung microbiome has not been fully explored, in part because only recently have people realized that there is a complex microbiome in the lung. Human studies demonstrate correlation between lung diseases and alterations of the airway microbiome, however there is a lack of direct evidence for causation. To examine this have developed a mouse model, where we can directly alter the lung microbiome. Our preliminary data demonstrate that the mouse lung, as is seen in many human lung diseases, has decreased microbial diversity during inflammation. In preliminary studies we have demonstrated that interaction with microbes commonly found in the pulmonary system influences the development of macrophages. Our long-term goal is to manipulate the airway microbiome to increase tolerance to lung disease. The overall objective of this proposal is to determine how damage-induced changes to the lung microbiome alter macrophage responses that are important in disease tolerance. Our data has allowed us to formulate the hypothesis that damage-induced changes in the lung microbiome decrease disease tolerance by altering the function of macrophages. To explore this hypothesis, we will determine how the airway microbiome is altered after lung damage (Aim 1), how exposure to specific airway microbes affect the function and development of macrophages (Aim 2), and how microbiota-induced changes to pulmonary macrophages influence host disease tolerance responses (Aim 3). This study will fundamentally alter our understanding of the influence of the lung microbiome on the ability of the innate immune response to increase tolerance of lung damage.
抽象的 胃酸吸入下呼吸道可导致肺炎、肺炎、急性肺损伤 (ALI),甚至更严重的ARDS。我们建议确定特定疾病的生存能力 主要由两个因素决定:抵抗力(改善疾病根源的能力)和耐受力( 应对疾病影响的能力)。许多先天免疫细胞类型在组织修复中发挥作用 回应。巨噬细胞极化成具有不同功能的几种亚型。最大的类别是 称为 M1(对感染反应很重要)和 M2(对组织修复和抗炎很重要)。 我们的数据表明,在稳态肺泡巨噬细胞中,肺组织驻留巨噬细胞是 向 M2 表型极化。我们的初步数据表明,酸吸入引起的 ALI 具有类似的作用。 影响作为感染,诱导 M1 表型。总的来说,这些数据表明,严重感染和 炎症改变巨噬细胞的编程,并降低其诱导修复表型的能力。 最近的研究表明,个体的肠道微生物群会影响对许多因素的反应。 疾病。然而,肺部微生物组的影响尚未得到充分探索,部分原因是仅 最近人们意识到肺部有一个复杂的微生物群。人类研究表明 肺部疾病与气道微生物组改变之间的相关性,但缺乏直接的证据 因果关系的证据。为了检查这一点,我们开发了一种小鼠模型,我们可以在其中直接改变肺部 微生物组。我们的初步数据表明,与许多人类肺部疾病一样,小鼠肺部 炎症期间微生物多样性降低。在初步研究中我们已经证明 与肺部系统中常见微生物的相互作用会影响 巨噬细胞。我们的长期目标是操纵气道微生物组以提高对肺部的耐受性 疾病。该提案的总体目标是确定损伤如何引起肺部变化 微生物组改变巨噬细胞反应,这对疾病耐受性很重要。我们的数据使我们能够 提出以下假设:损伤引起的肺部微生物组变化可减少疾病 通过改变巨噬细胞的功能来耐受。为了探索这个假设,我们将确定如何 肺损伤后气道微生物群发生改变(目标 1),暴露于特定气道微生物如何影响 巨噬细胞的功能和发育(目标 2),以及微生物群如何诱导肺部变化 巨噬细胞影响宿主的疾病耐受反应(目标 3)。这项研究将从根本上改变我们 了解肺部微生物群对增强先天免疫反应能力的影响 肺损伤的耐受性。

项目成果

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Amanda M Jamieson其他文献

Amanda M Jamieson的其他文献

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{{ truncateString('Amanda M Jamieson', 18)}}的其他基金

Central role of Caspase-8 in control of host tolerance and resistance mechanisms in pulmonary macrophage populations during severe respiratory infections
Caspase-8 在严重呼吸道感染期间肺巨噬细胞群宿主耐受和抵抗机制中的核心作用
  • 批准号:
    10668787
  • 财政年份:
    2023
  • 资助金额:
    $ 1.37万
  • 项目类别:
Influence of the lung microbiome on macrophage responses to lung damage
肺微生物组对巨噬细胞对肺损伤反应的影响
  • 批准号:
    9899749
  • 财政年份:
    2018
  • 资助金额:
    $ 1.37万
  • 项目类别:
Influence of the lung microbiome on macrophage responses to lung damage
肺微生物组对巨噬细胞对肺损伤反应的影响
  • 批准号:
    10377417
  • 财政年份:
    2018
  • 资助金额:
    $ 1.37万
  • 项目类别:
Project 3: Tolerance of Viral/Bacterial Co-infections
项目3:病毒/细菌混合感染的耐受性
  • 批准号:
    8813147
  • 财政年份:
    2016
  • 资助金额:
    $ 1.37万
  • 项目类别:

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组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
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