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）是退伍军人人口中发病率和死亡率的主要来源。尽管吸烟是主要的危险因素，但确定COPD发展和进展的确定仍然尚不完全理解。在此应用中，我们建议测试一种新型的COPD发病机理理论，该理论是基于小气道中粘膜免疫改变与COPD的关键参数（包括气道壁增厚，炎症细胞影响和气流限制）之间开发的。 IGA秘书IGA（SIGA）是气道中最丰富的免疫球蛋白，由聚合物免疫球蛋白受体（PIGR）传递到小气道表面，该受体在气道上皮细胞的基础表面上表达。在COPD中普遍存在的上皮重塑的环境中，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。在开发COPD样病理学之前，将小鼠暴露于主流香烟烟雾降低调节并降低气道中的Siga水平。在呼吸道缺乏SIGA的PIGR缺乏（PIGR - / - ）小鼠中，肺部出生时正常，成年后是正常的，但在6个月大时会发育类似COPD的气道和副型副疗程。这些结构性变化因暴露于香烟烟雾而恶化，并与细菌侵入气道上皮层，上皮NF-KB激活以及白细胞的影响/激活有关，o在人类中与COPD相似的发现。这些数据表明，气道表面上的SIGA在捍卫气道免受环境挑战中起着至关重要的作用，而粘膜免疫学改变了COPD的发展和进展。因此，我们假设在COPD中，在小气道表面降低了SIGA功能失调的粘膜免疫屏障，可以进入微生物和机载抗原进入气道上皮。结果，上皮中的持续/复发性NF-b激活驱动募集和激活白细胞的促炎性介质的表达。远端气道和肺实质中活化的白细胞（部分巨噬细胞）的积累会使COPD中的炎症状态延伸，并导致小气道重塑和肺气肿。要检验该假设，我们提出了以下具体目的：1）确定在肺中粘膜免疫屏障功能中断的小鼠中驱动小型气道重塑和肺气肿的机制，2）确定在PIGR缺乏小鼠肺中燃烧的细菌是否会减轻类似COPD的病理和3型病理的肺中的肺中燃烧，并影响了MIST-like-nike-nivine-nivine and-air Imstrif farff inff infffffffffffffffffffffffffe and 3 copb taff。 pigR缺乏小鼠中COPD样病理学发展的招募/激活。通过定义粘膜免疫对COPD的贡献，拟议的研究将改善对COPD发病机理的了解，并希望将导致新的有效疗法。