Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease
Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease
复制标题
慢性阻塞性肺疾病的异常上皮变异和异位炎症反应
DOI：
10.1165/rcmb.2021-0555oc
复制
发表时间：
2022
影响因子：
6.4
通讯作者：
Yamamoto Yusuke
中科院分区：
文献类型：
--
作者：
Watanabe Naoaki;Fujita Yu;Nakayama Jun;Mori Yutaro;Kadota Tsukasa;Hayashi Yusuke;Shimomura Iwao;Ohtsuka Takashi;Okamoto Koji;Araya Jun;Kuwano Kazuyoshi;Yamamoto Yusuke
肺上皮的表型改变已广泛涉及慢性阻塞性肺疾病（COPD）的发病机制，但由于肺实质和间质结构的复杂性，协调这种持续炎症过程的确切机制尚不清楚。为了确定促进COPD进展的多种肺驻留细胞类型和炎症细胞之间的细胞类型特异性机制和细胞-细胞相互作用，我们使用单细胞RNA测序技术分析了57,918个来自COPD患者、非COPD吸烟者和从不吸烟者肺部的细胞。我们预测了COPD中细胞分化的假时间和细胞间相互作用网络。尽管不吸烟者的上皮细胞成分相对均匀，但吸烟者组上皮细胞表现出广泛的异质性，特别是在肺泡2型（AT2）集群中。在通常被认为是肺泡祖细胞的AT2细胞中，我们发现了一个独特的亚群，它在COPD患者中增加，并特异性表达一系列趋化因子，包括CXCL1和CXCL8。轨迹分析显示炎症AT2细胞亚群遵循独特的分化路径，细胞间相互作用的预测模型推断炎症AT2细胞的细胞间网络显著增加。我们的研究结果确定了以前未识别的细胞亚群，并提供了对COPD发病机制的生物学和临床特征的见解。
Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type–specific mechanisms and cell–cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.