Microbial triggers and molecular mechanisms of Th17 mediated airway inflammation-Resubmission-1

Th17介导气道炎症的微生物触发因素和分子机制-Resubmission-1

基本信息

批准号：
9282599
负责人：
Sergei Borisovich Koralov
金额：
$ 64.06万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282599
关键词：
Age Airway Resistance Animals Antigen-Presenting Cells Asthma Automobile Driving Bacteria Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Bronchoscopy CD4 Positive T Lymphocytes Case-Control Studies Cells Chronic Chronic Obstructive Airway Disease Communities Comorbidity Data Disease Disease Progression Endothelial Cells Environment Epithelial Cells Flow Cytometry Gender Germ-Free Hyperactive behavior Immunologics Individual Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-17 Interruption Intervention Light Link Logistic Regressions Lung Lung Inflammation Lymphocyte Mainstreaming Measures Mediating Modeling Molecular Mucosal Immune Responses Mucous body substance Mus Neutrophil Infiltration Neutrophilia Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Phosphorylation Physiology Play Population Process Production Proteins Pulmonary Emphysema Pulmonary Inflammation Pulmonary Pathology Recruitment Activity Regulatory T-Lymphocyte Research Respiratory physiology Ribosomal RNA Role Sampling Severities Shapes Site Smoke Smoker Smoking Sputum Staining method Stains Stat3 protein Symptoms T-Lymphocyte Tissues airway inflammation airway remodeling base chemokine cigarette smoking cohort commensal microbes cytokine granulocyte gut microbiota high risk immunoregulation inflammatory lung disease insight interleukin-22 killings microbial microbiome microbiota mortality mouse model mucosal site mutant neutrophil new therapeutic target novel prevent public health relevance respiratory smooth muscle smoke inhalation transcription factor

项目摘要

DESCRIPTION (provided by applicant): T cell-driven inflammation is a key component of several inflammatory airway diseases, including chronic obstructive pulmonary disease (COPD). A recently identified subset of effector T cells, known as T helper type (Th)-17 cells, has been implicated in the pathogenesis of a number of chronic inflammatory conditions, including COPD. Yet, the role of these cells in chronic airway inflammation remains to be elucidated. Th17 cells secrete the cytokines IL-17 and IL-22 which act on surrounding epithelial and endothelial cells, as well as on resident antigen presenting cells, to elicit production of inflammatory cytokines and chemokines, leading to the recruitment of other inflammatory cells, including neutrophils. Differentiation of Th17 cells in the gut lumen has been closely linked to specific microbiota. However, whether the microbiome of other mucosal sites, such as the airways, is intimately linked to differentiation of Th17 cells at other sites is unknown. Airway neutrophilia is a common feature of COPD that parallels decline in lung function. Furthermore, COPD patients often present with high bacterial burden in the lower airways and the extent of airway colonization is closely associated with reduced lung function and enhanced co-morbidity. Our recent analysis of a cohort of smokers, a population that is at high risk of developing COPD, revealed that a distinct repertoire of airway microbiota is closely associated with elevated levels of pro-inflammatory cytokines and increased Th17 cells in the airways. Based on the paradigm that gut microbiota are critical in shaping the mucosal immune response in diseases such as inflammatory bowel disease, and in light of our preliminary studies, we hypothesize that airway microbiota plays a central role in directing the differentiation of Th17 cells, which in turn promoe chronic airway neutrophilia in COPD. To examine this, we will assess airway microbiota, cytokines and T cell populations in a unique cohort of asymptomatic smokers and smokers that develop COPD. To interrogate the connection between airway microbiota, Th17 cells and airway inflammation further we will take advantage of our novel mouse model that develops airway inflammation reminiscent of chronic airway inflammation seen in COPD. We will use this mouse model and a cigarette smoke inhalation model to gain mechanistic insight into the contribution of Th17-produced IL-17 and IL-22 to airway neutrophilia, mucus production, remodeling, emphysema and associated abnormalities in lung function. Furthermore, we will take advantage of our germ free facility to examine the contribution of airway microbiota and bacterial products in driving Th17-mediated airway inflammation and pathogenesis of COPD. We will accomplish this through re-introduction of bacterial communities or heat-killed bacteria into the recently rederived germ-free mice. These studies will provide new insight into the link between microbiota, Th17-mediated airway inflammation and COPD pathogenesis.

描述（由适用提供）：T细胞驱动的炎症是几种炎症性气道疾病的关键组成部分，包括慢性阻塞性肺部疾病（COPD）。最近在许多慢性炎症条件（包括COPD）的发病机理中实施了最近鉴定出的效应T细胞的子集，称为T辅助型（Th）-17细胞。然而，这些细胞在慢性气道感染中的作用尚待阐明。 Th17细胞向周围上皮细胞和内皮细胞以及驻留抗原呈递细胞的细胞因子IL-17和IL-22秘密，以引起炎症细胞因子和趋化因子，导致包括中性粒细胞在内的其他炎症细胞的募集。肠腔中Th17细胞的分化与特定的微生物群密切相关。但是，其他粘膜位点的微生物组（例如气道）是否与其他部位的Th17细胞的分化密切相关。气道嗜中性粒细胞是COPD的一个共同特征，该特征与肺功能的下降相似。此外，COPD患者经常在较低的气道中出现高细菌燃烧，气道定植的程度与肺功能降低和增强合并症密切相关。我们最近对一系列吸烟者的分析，该人群患COPD的高风险表明，气道微生物群的独特曲目与促炎性细胞因子的水平升高密切相关，并且气道中的Th17细胞增加。基于这样的范例，即肠道菌群对于塑造诸如炎症性肠病等疾病的粘膜免疫增强和初步研究至关重要，我们假设Airway Microbota在指导Th17细胞的差异化中起着TH17细胞的核心作用，该细胞在转向临时的Air ey Air Doy Air Dew oper Air道中心中性中性群。为此，我们将在独特的不对称吸烟者和发展COPD的吸烟者中评估气道微生物群，细胞因子和T细胞群体。为了询问气道微生物群之间的连接，TH17细胞和气道注射进一步询问我们将利用新型的小鼠模型来发展气道注入，让人联想到COPD中看到的慢性气道注入。我们将使用这种小鼠模型和香烟吸入模型来洞悉Th17产生的IL-17和IL-22对气道中性粒细胞增生，粘液产生，重塑，肺气肿以及肺功能中相关异常的贡献。此外，我们将利用我们的无菌设施来检查气道微生物群和细菌产物在驱动Th17介导的气道感染和COPD发病机理方面的贡献。我们将通过将细菌群落或热杀性细菌重新引入最近重新染色的小鼠来实现这一目标。这些研究将为微生物群，Th17介导的气道注射和COPD发病机理之间的联系提供新的见解。