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
• 负责人: Amanda M Jamieson
• 金额: $ 52.81万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899749
• 关键词: Acids; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Alveolar Macrophages; Anti-Inflammatory Agents; Area; Bacteria; Categories; Cells; Complex; Complication; Critical Illness; Data; Development; Disease; Etiology; Exposure to; Fluorescent in Situ Hybridization; Gastric Acid; Goals; Human; Immune; Immune response; In Vitro; Individual; Infection; Infection prevention; Inflammation; Injury; Innate Immune Response; Intestines; Lead; Lower respiratory tract structure; Lung; Lung diseases; Lung infections; Microbe; Mus; Patients; Phenotype; Plant Roots; Play; Pneumonia; Process; Publications; Pulmonary Inflammation; Research; Resistance; Role; Structure of parenchyma of lung; System; Techniques; Tissues; Viral; cell type; commensal bacteria; exposed human population; fitness; gut microbiome; immune function; in vitro Model; in vivo; in vivo Model; lung injury; lung microbiome; lung microbiota; macrophage; microbial; microbiome; microbiome alteration; microbiota; mouse model; next generation sequencing; pathogen; repaired; respiratory microbiome; respiratory microbiota; response; tissue repair; tissue-repair responses

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 胃酸进入下呼吸道会导致肺炎，肺炎，急性肺损伤 （ALI），甚至更严重的弧度。我们建议确定生存的能力 通过两个主要因素，抗药性（改善疾病根本原因的能力）和耐受性（ 能够应对疾病的影响）。许多先天免疫细胞类型在组织修复中起着作用 回答。巨噬细胞将具有不同功能的几种亚型偏振。最大的类别是 称为M1（对感染的响应很重要）和M2（对组织修复和抗炎作用很重要）。 我们的数据表明，在稳态大生气巨噬细胞中，肺的组织常驻巨噬细胞是 朝向M2 Phonotype的两极分化。我们的初步数据表明，酸抽吸引起的ALI具有相似的 作为感染的影响，诱导M1表型。这些数据共同表明，严重的感染和 炎症会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，个体的肠道微生物组会影响对许多人的反应 疾病。但是，尚未完全探索肺微生物组的影响，部分原因是 最近，人们意识到肺中有一个复杂的微生物组。人类研究表明 肺部疾病与气道微生物组的改变之间的相关性，但是缺乏直接 因果关系的证据。为了检查这一点，已经开发了一个鼠标模型，我们可以直接改变肺 微生物组。我们的初步数据表明，如许多人类肺部疾病所见，小鼠肺 炎症过程中微生物多样性的降低。在初步研究中，我们证明了 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的耐受性 疾病。该提案的总体目的是确定损伤引起的肺的变化 微生物组改变了在疾病耐受性中很重要的巨噬细胞反应。我们的数据使我们能够 提出这样的假设，即损伤引起的肺微生物组的变化减少了疾病 通过改变巨噬细胞的功能来容忍。为了探讨这一假设，我们将确定 气道微生物组在肺损伤后改变（AIM 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（AIM 2），以及微生物群诱导的肺变化 巨噬细胞会影响宿主疾病的耐受反应（AIM 3）。这项研究将从根本上改变我们的 了解肺微生物组对先天免疫反应增加能力的影响 肺损伤的耐受性。