Author:
Yu Hongjiao,Lin Yingnan,Zhong Yue,Guo Xiaolan,Lin Yuyin,Yang Siqi,Liu Jinglin,Xie Xinran,Sun Yaowei,Wang Dong,Li Bing,Ran Pixin,Dai Jianwei
Abstract
Abstract
Background
Particular matter 2.5 (PM2.5) is one of the most important air pollutant, and it is positively associated with the development of chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanisms through which PM2.5 promotes the development of COPD remains largely unknown.
Methods
Mouse alveolar destruction were determined by histological analysis of lung tissues and lung function test. Alveolar type II cells (AT2) to alveolar type I cells (AT1) transition in PM2.5-induced COPD mouse model was confirmed via immunofluorescence staining and qPCR analysis. The differentially expressed genes in PM2.5-induced COPD mouse model were identified by RNA-sequencing of alveolar epithelial organoids and generated by bioinformatics analysis.
Results
In this study, we found that 6 months exposure of PM2.5 induced a significantly decreased pulmonary compliance and resulted in pulmonary emphysema in mice. We showed that PM2.5 exposure significantly reduced the AT2 to AT1 cell transition in vitro and in vivo. In addition, we found a reduced expression of the intermediate AT2-AT1 cell process marker claudin 4 (CLDN4) at day 4 of differentiation in mouse alveolar organoids treated with PM2.5, suggesting that PM2.5 exposure inhibited AT2 cells from entering the transdifferentiation process. RNA-sequencing of mouse alveolar organoids showed that several key signaling pathways that involved in the AT2 to AT1 cell transition were significantly altered including the Wnt signaling, MAPK signaling and signaling pathways regulating pluripotency of stem cells following PM2.5 exposure.
Conclusions
In summary, these data demonstrate a critical role of AT2 to AT1 cell transition in PM2.5-induced COPD mouse model and reveal the signaling pathways that potentially regulate AT2 to AT1 cell transition during this process. Our findings therefore advance the current knowledge of PM2.5-induced COPD and may lead to a novel therapeutic strategy to treat this disease.
Funder
Project of the State Key Laboratory of Respiratory Disease, Guangzhou Medical University
National Natural Science Foundation of China
Natural Science Foundation of Guangdong Province, China
Publisher
Springer Science and Business Media LLC
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