Mechanisms driving airway inflammation in chronic lung disease

在目前的资助期间，我们发现在小气道中获得性黏膜免疫缺陷是一种 慢性阻塞性肺疾病(COPD)的中心特征。我们现在建议研究机制 通过该第一道寄主防御线的损伤导致后续寄主防御线的持续激活 防御(先天免疫和适应性免疫)，从而推动COPD的进展。尽管已经很清楚了 几年来，COPD的病理开始于小阻力气道，其机制联系着小 呼吸道和实质病理尚不清楚。小气道上皮产生粘膜宿主 通过各种机制进行防御，包括将免疫球蛋白输送到呼吸道表面。向下- 二聚体转运所需的聚合物免疫球蛋白受体(PIgR)表达的调节 慢性阻塞性肺疾病患者气道基底外侧至管腔表面的免疫球蛋白选择性减少 呼吸道表面产生分泌性免疫球蛋白A(SIgA)屏障。慢性阻塞性肺疾病患者的个体小气道 患者，SIgA降低与细菌侵入上皮层，激活NF-κB，以及 炎症/免疫细胞的涌入。这些致病特征可模拟为pIgR缺陷(pIgR-/-) 小鼠，粘膜表面缺乏SIgA。像慢性阻塞性肺病患者一样，这些小鼠发展为进展性的 肺气肿和小气道重塑，以及呼吸道上皮层内细菌的证据， 上皮性核因子-κB的激活，以及炎症/免疫细胞的流入。无菌饲养pIgR-/-小鼠 条件、广谱口服抗生素治疗和中性粒细胞减少可减少肺部病理改变。在……里面 此外，pIgR-/-小鼠出现淋巴细胞聚集，包括CD4+和Th17+T细胞增加，以及 肺部的三级淋巴结构，特别是高龄患者(类似于患有严重COPD的人)， 同时，树突状细胞群向增加的单核细胞来源的树突状细胞转变。 淋巴细胞耗竭减少pIgR-/-小鼠COPD样病理及广谱治疗 抗生素使DC群体正常化，减少T细胞的流入，并消除第三级淋巴系统的积聚 结构，从而暗示先天免疫和获得性免疫在该模型中的COPD样病理中。 总而言之，现有数据表明，多层呼吸道宿主防御结构的每一层， 进化为保护脆弱的粘膜表面，在慢性阻塞性肺疾病中变得功能失调。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， 导致先天免疫细胞的持续招募和激活以及适应性的病理性激活 免疫，协同作用推动呼吸道重塑和肺气肿。具体目标是：1)调查 上皮NF-κB在粘膜免疫小鼠天然免疫和获得性免疫激活中的作用 缺乏，2)确定T淋巴细胞在慢性阻塞性肺疾病样病理发展中的作用。 粘膜免疫缺陷，以及3)确定肺部树突状细胞亚群的改变是否在 获得性免疫激活与慢性阻塞性肺疾病的持续性炎症详细了解两国之间的相互作用 推动COPD进展的粘膜免疫、先天免疫和获得性免疫需要开发新的方法来限制 进行性组织损伤，同时在肺部维持足够的宿主防御。

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.