Impaired AT2 to AT1 cell transition in PM2.5-induced mouse model of chronic obstructive pulmonary disease

Respiratory Research

Yuyin Lin¹  Xiaolan Guo¹  Xinran Xie¹  Yue Zhong¹  Yaowei Sun¹  Yingnan Lin¹  Siqi Yang¹  Jinglin Liu¹  Hongjiao Yu¹  Bing Li¹  Jianwei Dai¹  Dong Wang²  Pixin Ran² 

[1] Guangzhou Medical University-Guangzhou Institute of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University;State Key Lab of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University;

关键词: PM2.5;    COPD;    Alveolar epithelium;    AT2-to-AT1 transition;   

DOI  :  10.1186/s12931-022-01996-w

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown