Distal-to-Proximal Re-patterning of Small Airway Epithelium in Smoking-associated Chronic Obstructive Pulmonary Disease. Homo sapiens

The proximal-distal patterning program determines unique structural and functional properties of proximal and distal airways in the adult lung. Based on the knowledge that remod-eling of distal airways is the major pathologic feature of chronic obstructive pulmonary disease (COPD), and that small airway epithelium (SAE), which covers distal airways, is the primary site of the initial smoking-induced changes relevant to COPD pathogenesis, we hypothesized that in COPD smokers, the SAE transcriptome loses its region-specific biologic identity and takes on the transcriptional pattern of the proximal airways. By analyzing human airway epithelium col-lected by bronchoscopic brushings from proximal and distal airways of healthy smokers, proxi-mal and distal airway epithelial transcriptome signatures were identified. Dramatic smoking-dependent suppression of distal signature paralleled by acquisition of the proximal airway epithe-lial phenotype was found in the SAE of COPD smokers. Distal-proximal re-patterning observed in the SAE of smokers in vivo was reproduced in vitro by stimulating SAE basal cells (BC), the stem/progenitor cells of the SAE, with EGF, a growth factor up-regulated in airway epithelium by smoking. Together, this study identifies distal-proximal SAE re-patterning as a characteristic feature of small airway disordering in COPD smokers potentially driven by EGF/EGFR-mediated reprogramming of SAE BC stem/progenitor cells. Overall design: In this study, distal and proximal human airway epithelial transcriptome signatures were identified by genome-wide analysis of the epithelial samples obtained by bronchoscopic brushings from the distal and proximal airways of healthy nonsmokers. Expression of the identified distal and proximal signatures were then analyzed in the small airway epithelium (SAE) of smokers with COPD compared to that of healthy smokers and healthy nonsmokers. A dramatic smoking-dependent suppression of the distal signature expression accompanied by up-regulation of the proximal signature genes was observed in the SAE of COPD smokers, a novel pathologic feature of COPD-associated small airway disordering designated “distal-proximal re-patterning” of the SAE.

近端-远端模式化程序决定了成年肺内近端与远端气道各自独特的结构与功能特性。基于远端气道重塑是慢性阻塞性肺疾病（COPD）的主要病理特征，且覆盖远端气道的小气道上皮（SAE）是吸烟诱导的与COPD发病机制相关的初始改变的主要发生部位这一认知，本研究提出假说：在COPD吸烟者体内，小气道上皮的转录组会丧失其区域特异性的生物学特征，并转而呈现近端气道的转录模式。通过对健康吸烟者近端与远端气道经支气管刷检获取的人气道上皮样本进行分析，本研究鉴定出了近端与远端气道上皮的转录组特征标签。在COPD吸烟者的小气道上皮中，研究人员观察到：远端特征标签呈现出显著的吸烟依赖性抑制，同时伴随近端气道上皮表型的获得。吸烟者体内小气道上皮中观察到的远端-近端模式重塑现象，可通过用吸烟可诱导其在气道上皮中表达上调的生长因子——表皮生长因子（EGF），刺激小气道上皮的干/祖细胞——基底细胞（BC），在体外重现。综上，本研究确认：远端-近端小气道上皮模式重塑是COPD吸烟者小气道功能紊乱的特征性表现，其潜在驱动机制为表皮生长因子/表皮生长因子受体（EGFR）介导的小气道上皮基底细胞干/祖细胞重编程。研究设计：本研究首先通过对健康非吸烟者远端与近端气道经支气管刷检获取的上皮样本进行全基因组分析，鉴定出人类远端与近端气道上皮的转录组特征标签。随后，本研究对比分析了COPD吸烟者、健康吸烟者与健康非吸烟者的小气道上皮（SAE）中上述已鉴定的远端与近端特征标签的表达水平。研究人员在COPD吸烟者的小气道上皮中观察到：远端特征标签的表达呈现显著的吸烟依赖性抑制，同时伴随近端特征标签基因的表达上调；这一现象被定义为小气道上皮的"远端-近端模式重塑"，是COPD相关小气道功能紊乱的全新病理特征。