Mechanisms driving airway inflammation in chronic lung disease

慢性肺病气道炎症的驱动机制

• 批准号: 8974370
• 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/8974370
• 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; Fibrosis; Health; 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; environmental tobacco smoke exposure; germ free condition; improved; inhibitor/antagonist; leukocyte activation; macrophage; microorganism; mortality; neutrophil; novel; pathogen; protein transport; 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）： 慢性阻塞性肺病（COPD）是退伍军人发病率和死亡率的主要来源。尽管吸烟是主要危险因素，但慢性阻塞性肺病发生和进展的决定因素仍不完全清楚。在本申请中，我们建议测试一种新的慢性阻塞性肺病发病机制理论，该理论是基于小气道粘膜免疫改变与慢性阻塞性肺病关键参数（包括气道壁增厚、炎症细胞流入和气流受限）之间的显着相关性而开发的。分泌型 IgA (SIgA) 是气道中最丰富的免疫球蛋白，由聚合免疫球蛋白受体 (pIgR) 递送至小气道表面，该受体表达于气道上皮细胞的基底外侧表面。在慢性阻塞性肺病中普遍存在的上皮重塑的情况下，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。在出现慢性阻塞性肺病样病理之前，将小鼠暴露于主流香烟烟雾会下调 pIgR 表达并降低气道中的 SIgA 水平。 pIgR 缺陷 (pIgR-/-) 小鼠的气道中缺乏 SIgA，其肺部在出生时和成年初期是正常的，但在 6 个月大时会自发地出现类似 COPD 的气道和实质重塑。这些结构变化因接触香烟烟雾而恶化，并与气道上皮层的细菌侵入、上皮 NF-kB 激活和白细胞流入/激活有关，与慢性阻塞性肺病患者的发现相似。这些数据表明，气道表面的 SIgA 在保护气道免受环境挑战方面发挥着重要作用，并且粘膜免疫的改变有助于 COPD 的发生和进展。因此，我们推测，在慢性阻塞性肺病中，小气道表面的粘膜免疫屏障功能失调，SIgA 减少，使得微生物和空气中的抗原能够进入气道上皮。结果，上皮细胞中持续/反复的 NF-κB 激活驱动促炎介质的表达，从而招募和激活白细胞。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慢性阻塞性肺病的炎症状态持续存在，并导致小气道重塑和肺气肿。为了检验这一假设，我们提出以下具体目标：1) 确定肺部粘膜免疫屏障功能受损的小鼠中驱动小气道重塑和肺气肿的机制，2) 确定改变 pIgR 缺陷小鼠肺部的细菌负荷是否会改变 COPD 样病理的发生和进展，3) 确定 NF-kB 激活和巨噬细胞的影响 pIgR 缺陷小鼠中 COPD 样病理学发展的募集/激活。通过确定粘膜免疫改变对慢性阻塞性肺病的影响，拟议的研究将加深对慢性阻塞性肺病发病机制的了解，并有望带来新的有效疗法。