Mechanisms driving airway inflammation in chronic lung disease

慢性肺病气道炎症的驱动机制

• 批准号: 8733873
• 负责人: Timothy S. Blackwell
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733873
• 关键词: Address; Age-Months; Alveolar Macrophages; Antibiotics; Antigens; Automobile Driving; Bacteria; Birth; Breathing; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Cleaved cell; Complement Factor B; Data; Development; Disease; Disease Progression; Distal; Employee Strikes; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Exposure to; Fibrosis; Host Defense; Human; IgA Deficiency; Immune; Immunoglobulin A; Immunoglobulins; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Invaded; Irritants; Lead; Leukocytes; Lung; Macrophage Activation; Mainstreaming; Mediating; Mediator of activation protein; Methodology; Morbidity - disease rate; Mucociliary Clearance; Mucosal Immunity; Mucous Membrane; Mus; Nontypable Haemophilus influenza; Nuclear; Oxidants; Particulate; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Polymeric Immunoglobulin Receptors; Population; Pulmonary Emphysema; Recruitment Activity; Recurrence; Risk Factors; Role; Secretory Immunoglobulin A; Signal Transduction; Source; Structure of parenchyma of lung; Surface; Testing; Transgenic Mice; Veterans; Work; airway epithelium; airway inflammation; airway remodeling; antimicrobial peptide; base; cigarette smoking; cigarette smoking; defined contribution; effective therapy; end stage disease; germ free condition; improved; inhibitor/antagonist; leukocyte activation; macrophage; microorganism; mortality; neutrophil; novel; pathogen; protein transport; public health relevance; receptor expression; smoking cessation; theories; upstream kinase; young adult

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a major source of morbidity and mortality in the Veteran population. Although cigarette smoking is the major risk factor, determinants of COPD development and progression remain incompletely understood. In this application, we propose to test a novel theory of COPD pathogenesis that we developed based on striking correlations between altered mucosal immunity in small airways and key parameters of COPD, including airway wall thickening, inflammatory cell influx, and airflow limitation. Secretory IgA (SIgA), the most abundant immunoglobulin in the airways, is delivered to the surface of small airways by the polymeric immunoglobulin receptor (pIgR), which is expressed on the basolateral surface of airway epithelial cells. In the setting of epithelial remodeling, which is pervasive in COPD, our preliminary data indicate that epithelial cells down-regulate pIgR expression and are no longer able to maintain a normal mucosal immune barrier. Exposure of mice to mainstream cigarette smoke down-regulates pIgR expression and reduces SIgA levels in the airways prior to development of COPD-like pathology. In pIgR deficient (pIgR-/-) mice, which lack SIgA in their airways, lungs are normal at birth and young adulthood but spontaneously develop COPD-like airway and parenchymal remodeling by 6 months of age. These structural changes are worsened by exposure to cigarette smoke and are associated with bacterial invasion of the airway epithelial layer, epithelial NF-kB activation, and influx/activation of leukocytes, similar o findings in humans with COPD. These data suggest that SIgA on the airway surface plays an essential role in defending the airway from environmental challenges and that altered mucosal immunity contributes to development and progression of COPD. Therefore, we hypothesize that in COPD a dysfunctional mucosal immune barrier with reduced SIgA on the surface of small airways allows access of microorganisms and airborne antigens to the airway epithelium. As a result, persistent/recurrent NF-¿B activation in the epithelium drives expression of pro- inflammatory mediators that recruit and activate leukocytes. Accumulation of activated leukocytes (particularly macrophages) in the distal airways and lung parenchyma perpetuates the inflammatory state in COPD and leads to small airway remodeling and emphysema. To test this hypothesis, we propose the following specific aims: 1) to identify mechanisms that drive small airway remodeling and emphysema in mice with disrupted mucosal immune barrier function in the lungs, 2) to determine whether altering the bacterial burden in lungs of pIgR deficient mice alters development and progression of COPD-like pathology, and 3) to define the impact of NF-kB activation and macrophage recruitment/activation on development of COPD-like pathology in pIgR deficient mice. By defining the contribution of altered mucosal immunity to COPD, proposed studies will result in improved understanding of COPD pathogenesis and hopefully will lead to new effective therapies.

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是退伍军人人群发病率和死亡率的主要来源。尽管吸烟是COPD的主要危险因素，但COPD发展和进展的决定因素仍不完全清楚。在本申请中，我们提出测试一种新的COPD发病机制理论，该理论是基于小气道粘膜免疫改变与COPD关键参数（包括气道壁增厚、炎性细胞内流和气流限制）之间的显著相关性而开发的。分泌型伊加（SIgA）是气道中最丰富的免疫球蛋白，通过多聚免疫球蛋白受体（pIgR）递送到小气道表面，所述多聚免疫球蛋白受体在气道上皮细胞的基底外侧表面上表达。在COPD中普遍存在的上皮重塑的背景下，我们的初步数据表明上皮细胞下调pIgR表达，并且不再能够维持正常的粘膜免疫屏障。暴露于主流香烟烟雾的小鼠在COPD样病理学发展之前下调气道中的pIgR表达并降低SIgA水平。在pIgR缺陷（pIgR-/-）小鼠中，其气道中缺乏SIgA，肺在出生时和青年期是正常的，但在6个月龄时自发地发生COPD样气道和实质重塑。这些结构变化因暴露于香烟烟雾而恶化，并且与气道上皮层的细菌侵入、上皮NF-kB活化和白细胞的流入/活化相关，这与患有COPD的人类中的发现相似。这些数据表明，气道表面上的SIgA在保护气道免受环境挑战方面起着至关重要的作用，并且改变的粘膜免疫有助于COPD的发生和进展。因此，我们假设在COPD中，小气道表面上的SIgA减少的粘膜免疫屏障功能障碍允许微生物和空气传播的抗原进入气道上皮。因此，上皮中持续/复发的NF-B活化驱动促炎介质的表达，所述促炎介质募集并活化白细胞。活化的白细胞（特别是巨噬细胞）在远端气道和肺实质中的积累使COPD中的炎症状态持续，并导致小气道重塑和肺气肿。为了检验这一假设，我们提出了以下具体目标：1）鉴定在肺中具有破坏的粘膜免疫屏障功能的小鼠中驱动小气道重塑和肺气肿的机制，2）确定改变pIgR缺陷小鼠的肺中的细菌负荷是否改变COPD样病理的发展和进展，和3）确定NF-κ B活化和巨噬细胞募集/活化对pIgR缺陷小鼠中COPD样病理发展的影响。通过定义改变的粘膜免疫对COPD的贡献，拟议的研究将导致对COPD发病机制的更好理解，并有望导致新的有效治疗。