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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：
10377417
负责人：
Amanda M Jamieson
金额：
$ 43.86万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377417
关键词：
Acids Acute Lung Injury Acute Respiratory Distress Syndrome Address 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 Persons Phenotype Plant Roots Play Pneumonia Process Publications Pulmonary Inflammation Research Resistance Role 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 lung repair macrophage microbial microbiome microbiome alteration microbiota mouse model next generation sequencing pathogen repair function repaired respiratory microbiome respiratory microbiota response tissue repair tissue-repair responses

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)，甚至更严重的ARDS。我们认为，特定疾病的生存能力是由根据两个主要因素，抵抗力(改善疾病根本原因的能力)和耐受性( 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。巨噬细胞分化为几种不同功能的亚型。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)。我们的数据显示，在稳定状态下，肺组织中驻留的巨噬细胞--肺泡巨噬细胞偏向M2表型。我们的初步数据显示，酸吸入诱导的ALI具有类似的作为感染的影响，诱导出M1表型。总而言之，这些数据表明，严重感染和炎症改变了巨噬细胞的编程，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群会影响对许多疾病。然而，肺部微生物群的影响还没有得到充分的研究，部分原因是最近，人们意识到肺里有一个复杂的微生物群。人体研究表明肺部疾病与呼吸道微生物群改变的相关性，但缺乏直接的相关性因果关系的证据。为了检验这一点，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，小鼠的肺，就像在许多人类肺部疾病中看到的那样，在炎症过程中降低了微生物多样性。在初步研究中，我们已经证明与肺脏中常见微生物的相互作用影响着巨噬细胞。我们的长期目标是操纵呼吸道微生物群以增加对肺的耐受性疾病。这项建议的总体目标是确定损伤对肺的影响微生物群改变巨噬细胞的反应，而巨噬细胞反应在疾病耐受性中很重要。我们的数据使我们能够阐明损伤引起的肺部微生物群变化可减少疾病的假说通过改变巨噬细胞的功能来耐受。为了探索这一假设，我们将确定肺损伤后呼吸道微生物群改变(目标1)，暴露于特定的呼吸道微生物如何影响巨噬细胞的功能和发育(目标2)，以及微生物区系如何诱导肺组织的变化巨噬细胞影响宿主疾病耐受反应(目标3)。这项研究将从根本上改变我们的了解肺部微生物群对先天免疫应答增强能力的影响对肺损伤的耐受性。