Division of Pulmonary and Critical Care Medicine.
Department of Medicine.
Am J Respir Crit Care Med. 2023 Nov 15;208(10):1101-1114. doi: 10.1164/rccm.202210-1865OC.
Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.
慢性阻塞性肺疾病（COPD）与高发病率、高死亡率和高医疗成本相关。香烟烟雾是一个致病因素；然而，并非所有重度吸烟者都会发展为 COPD。微生物定植和感染是疾病进展到晚期的一个促成因素。我们研究了轻度至中度 COPD 是否会发生下呼吸道失调，并分析了对 COPD 发病机制的可能机制贡献。我们招募了 57 名有>10 包年吸烟史的患者：26 名有生理上的 COPD 证据，31 名有正常的肺功能（吸烟者对照）。支气管镜检查采集上呼吸道、下呼吸道和环境背景样本。通过 16S rRNA 基因测序、全基因组、RNA 宏转录组和宿主 RNA 转录组分析样本。使用临床前小鼠模型评估香烟烟雾和失调对下呼吸道炎症损伤的贡献。与吸烟者对照相比，微生物组分析表明 COPD 患者的下呼吸道富含常见的口腔共生菌。下呼吸道宿主转录组学显示了炎症和肿瘤发生标志物的差异，例如在轻度至中度 COPD 中，IL-17、IL-6、ERK/MAPK、PI3K、MUC1 和 MUC4 的上调。最后，在暴露于香烟烟雾的临床前小鼠模型中，常见口腔共生菌的下呼吸道失调会加剧炎症损伤，揭示了与 COPD 患者相似的转录组特征。在吸烟暴露的情况下，下呼吸道失调会导致 COPD 早期的炎症损伤。针对下呼吸道微生物组与戒烟相结合可能具有潜在的治疗相关性。
