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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（由申请人提供）：T细胞驱动的炎症是包括慢性阻塞性肺病（COPD）在内的几种炎症性气道疾病的关键组成部分。最近鉴定的效应T细胞亚群，称为T辅助型（Th）-17细胞，与许多慢性炎症性疾病（包括COPD）的发病机制有关。然而，这些细胞在慢性气道炎症中的作用仍有待阐明。Th 17细胞分泌细胞因子IL-17和IL-22，它们作用于周围的上皮细胞和内皮细胞，以及驻留的抗原呈递细胞，以引起炎性细胞因子的产生，趋化因子，导致其他炎性细胞，包括中性粒细胞的招聘。肠腔中Th 17细胞的分化与特定的微生物群密切相关。然而，其他粘膜部位（如气道）的微生物组是否与其他部位的Th 17细胞分化密切相关尚不清楚。呼吸道嗜酸性粒细胞增多是COPD的常见特征，与肺功能下降平行。此外，COPD患者通常在下呼吸道中存在高细菌负荷，并且呼吸道定植的程度与肺功能降低和合并症增加密切相关。我们最近对一组吸烟者（一个患COPD的高风险人群）的分析显示，气道微生物群的独特组成与气道中促炎细胞因子水平升高和Th 17细胞增加密切相关。基于肠道微生物群在炎症性肠病等疾病中塑造粘膜免疫应答至关重要的范式，并根据我们的初步研究，我们假设气道微生物群在指导Th 17细胞分化中起着核心作用，这反过来又促进了COPD中的慢性气道嗜酸性粒细胞。为了检验这一点，我们将评估无症状吸烟者和发展为COPD的吸烟者的独特队列中的气道微生物群、细胞因子和T细胞群。为了进一步探究气道微生物群，Th 17细胞和气道炎症之间的联系，我们将利用我们的新型小鼠模型，该模型发展出令人想起COPD中所见的慢性气道炎症的气道炎症。我们将使用该小鼠模型和香烟烟雾吸入模型来获得对Th 17产生的IL-17和IL-22对气道嗜中性粒细胞、粘液产生、重塑、肺气肿和肺功能相关异常的贡献的机制性见解。此外，我们将利用我们的无菌设施来研究气道微生物群和细菌产物在驱动Th 17介导的气道炎症和COPD发病机制中的作用。我们将通过将细菌群落或热灭活细菌重新引入最近再衍生的无菌小鼠来实现这一目标。这些研究将为微生物群，Th 17介导的气道炎症和COPD发病机制之间的联系提供新的见解。