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.
摘要 胃酸吸入下呼吸道可导致肺炎、肺炎、急性肺损伤 (ALI)甚至是更严重的ARDS。我们认为,在特定疾病中生存的能力是由 两个主要因素,抗性(改善疾病根源的能力)和耐受性( (1)科普疾病影响的能力)。许多先天免疫细胞类型在组织修复中发挥作用 应答宏程序划分为几个具有不同功能的子程序。最大的类别是 被称为M1(对感染的反应很重要)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,肺的组织驻留巨噬细胞, 向M2表型极化。我们的初步数据表明,酸吸入诱导的ALI具有类似的 感染,诱导M1表型。总的来说,这些数据表明,严重感染和 炎症改变了巨噬细胞的编程,并降低了它们诱导修复表型的能力。 最近的研究表明,一个人的肠道微生物组会影响对许多疾病的反应。 疾病然而,肺部微生物组的影响尚未得到充分研究,部分原因是 最近人们意识到肺部有一个复杂的微生物组。人体研究表明 肺部疾病和气道微生物组改变之间的相关性,然而,缺乏直接的 因果关系的证据。为了验证这一点,我们开发了一个小鼠模型,在那里我们可以直接改变肺, 微生物组我们的初步数据表明,小鼠肺,正如在许多人类肺部疾病中所看到的那样, 在炎症期间减少了微生物多样性。在初步研究中,我们已经证明, 与肺系统中常见的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,以增加对肺结核的耐受性。 疾病本提案的总体目标是确定损伤诱导的肺变化 微生物组改变巨噬细胞反应,这在疾病耐受性中很重要。我们的数据使我们能够 提出损伤诱导的肺部微生物组变化可减少疾病的假设 通过改变巨噬细胞的功能来增强耐受性。为了探索这一假设,我们将确定 肺损伤后气道微生物组改变(目标1),暴露于特定的气道微生物如何影响 巨噬细胞的功能和发育(目的2),以及微生物群如何诱导肺 巨噬细胞影响宿主疾病耐受性应答(目的3)。这项研究将从根本上改变我们的 了解肺部微生物组对先天免疫应答能力的影响, 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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