Mechanisms driving airway inflammation in chronic lung disease

慢性肺病气道炎症的驱动机制

• 批准号: 10216169
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216169
• 关键词: Adaptive Immune System; Adoptive Transfer; Airway Resistance; Antibiotics; Antigens; Automobile Driving; Bacteria; CD4 Positive T Lymphocytes; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Data; Defect; Dendritic Cells; Development; Disease; Disease Progression; Disease model; Down-Regulation; Elderly; Epithelial; Epithelial Cells; Exposure to; Funding; Generations; Host Defense; Human; Immune; Immunity; Immunoglobulin A; Immunoglobulin M; Immunoglobulins; Impairment; Individual; Inflammation; Inflammatory; Interleukin-17; Intervention; Knowledge; Lead; Leukocyte Elastase; Link; Lung; Lymphocyte; Lymphocyte Depletion; Mediating; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; Oral; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Polymeric Immunoglobulin Receptors; Population; Production; Pulmonary Emphysema; Pulmonary Pathology; Role; Secretory Immunoglobulin A; Signal Transduction; Structure; Surface; T-Cell Depletion; T-Lymphocyte; Testing; Veterans; Work; adaptive immunity; airway epithelium; airway inflammation; airway remodeling; cytokine; dimer; end stage disease; experimental study; exposure to cigarette smoke; germ free condition; immune activation; monocyte; neutrophil; novel; receptor expression; recruit; smoking cessation; tertiary lymphoid organ; tissue injury; upstream kinase

In the current funding period, we showed that acquired defects in mucosal immunity in small airways are a central feature of chronic obstructive pulmonary disease (COPD). We now propose to investigate mechanisms by which impairment of this first line of host defense leads to persistent activation of subsequent lines of host defense (innate and adaptive immunity), thus driving COPD progression. Although it has been clear for several years that COPD pathology begins in the small resistance airways, the mechanisms linking small airway and parenchymal pathology have been obscure. The small airway epithelium generates mucosal host defense by a variety of mechanisms, including transporting immunoglobulins to the airway surface. Down- regulation of polymeric immunoglobulin receptor (pIgR) expression, which is required for transport of dimeric IgA from the basolateral to luminal surface of the airway, is selectively reduced in COPD and impairs generation of the secretory IgA (SIgA) barrier on the airway surface. In individual small airways of COPD patients, reduced SIgA is associated with bacterial invasion into the epithelial layer, activation of NF-κB, and influx of inflammatory/immune cells. These pathogenic features can be modeled in pIgR deficient (pIgR-/-) mice, which lack SIgA on mucosal surfaces. Like COPD patients, these mice develop progressive emphysema and small airways remodeling, along with evidence of bacteria within the airway epithelial layer, epithelial NF-κB activation, and an influx of inflammatory/immune cells. Raising pIgR-/- mice in germ-free conditions, treatment with broad spectrum oral antibiotics, and neutrophil depletion reduce lung pathology. In addition, pIgR-/- mice develop lymphocyte accumulation, including increased CD4+ and Th17+ T cells, and tertiary lymphoid structures in the lungs, particularly with advanced age (similar to humans with severe COPD), along with a shift in the dendritic cell population towards increased monocyte-derived dendritic cells. Lymphocyte depletion reduces COPD-like pathology in pIgR-/- mice and treatment with broad spectrum antibiotics normalizes DC populations, reduces T cell influx, and eliminates accumulation of tertiary lymphoid structures, thus implicating both innate and adaptive immunity in the COPD-like pathology in this model. Together, available data suggests that each layer of the multi-layered airway host defense structure, which evolved to protect vulnerable mucosal surfaces, becomes dysfunctional in COPD. Therefore, we hypothesize that disruption of the SIgA immune barrier in small airways results in inflammatory signaling in epithelial cells, leading to persistent recruitment and activation of innate immune cells and pathologic activation of adaptive immunity, which synergize to drive airway remodeling and emphysema. Specific Aims are: 1) to investigate the role of epithelial NF-κB in driving innate and adaptive immune activation in mice with mucosal immune deficiency, 2) to identify the role of T lymphocytes in development of COPD-like pathology in mice with mucosal immune deficiency, and 3) to determine whether altered dendritic cell subsets in the lungs mediate adaptive immune activation and sustained inflammation in COPD. Detailed knowledge of interactions between mucosal, innate, and adaptive immunity that drive COPD progression is required to develop new ways to limit progressive tissue injury while maintaining adequate host defense in the lungs.

在当前的资金期间，我们表明在小气道中获得的粘膜免疫缺陷是 慢性阻塞性肺疾病（COPD）的主要特征。我们现在建议调查机制 通过哪种损害，第一线宿主防御导致随后的主机持续激活 国防（先天和适应性免疫学），因此推动了COPD的进展。虽然很清楚 COPD病理学从小型阻力气道开始的几年，这些机制与小 气道和副型病理学一直是晦涩的。小气道上皮会产生粘膜宿主 通过多种机制进行防御，包括将免疫球蛋白运输到气道表面。向下- 调节聚合物免疫球蛋白受体（PIGR）表达，这是二聚体运输所必需的 IgA从气道的基底外侧到腔表面，在COPD中选择性降低并损害 在气道表面上产生秘密IGA（SIGA）屏障。在COPD的单个小气道中 患者的SIGA降低与细菌侵入上皮层有关，NF-κB的激活和 炎症/免疫细胞的影响。这些病原特征可以在不足的PIGR中建模（PIGR - / - ） 小鼠，在粘膜表面缺乏Siga。像COPD患者一样，这些小鼠发展 肺气肿和小气道重塑，以及气道上皮层中细菌的证据 上皮NF-κB激活和炎症/免疫细胞的影响。在无菌中升高pigr - / - 小鼠 疾病，广谱口服抗生素的治疗以及中性粒细胞耗竭可减少肺病理学。在 另外，PIGR - / - 小鼠会形成淋巴细胞积累，包括CD4+和Th17+ T细胞增加，以及 肺中的三级淋巴结构，尤其是高龄（类似于患有严重COPD的人）， 随着树突状细胞种群向增加单核细胞衍生的树突状细胞的转变。 淋巴细胞耗竭可降低PIGR - / - 小鼠中的COPD样病理，并用广谱治疗 抗生素使直流种群归一化，减少了T细胞的影响并消除了三级淋巴样的积累 因此，在该模型中类似COPD的病理学中，结构是隐含的先天和适应性免疫学。 总之，可用的数据表明多层气道宿主防御结构的每一层 进化为保护脆弱的粘膜表面，在COPD中变得功能失调。因此，我们假设 小气道中SIGA免疫屏障的破坏会导致上皮细胞的炎症信号传导， 导致持续募集和激活先天免疫小球和自适应的病理激活 免疫力，协同驱动气道重塑和肺气肿。具体目的是：1）调查 上皮NF-κB在粘膜免疫反应的小鼠中驱动先天和适应性免疫反应中的作用 缺乏症，2）确定T淋巴细胞在小鼠中的COPD样病理发展中的作用 粘膜免疫缺陷和3）确定肺中的树突状细胞亚群是否改变 自适应免疫激活和COPD中的持续注射。详细了解互动之间的互动 需要驱动COPD进展的粘膜，先天和适应性免疫才能开发出新的方法来限制 进行性组织损伤，同时保持肺部充足的宿主防御。