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

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.

[Retracted] The Efficacy and Safety of Budesonide/Glycopyrronium/Formoterol in the Treatment of COPD in the Elderly

“…At present, some progress has been made in the relationship between aging, and chronic obstructive pulmonary disease and pulmonary fibrosis [ 48 ]. However, the specific molecular mechanism and functional relationship of aging in the occurrence and the development of chronic obstructive pulmonary disease and pulmonary fibrosis are not completely clear [ 49 ]. Finding these molecular mechanisms and functional relationships may bring hope to cure these diseases [ 50 ].…”

Lung Organoids for Hazard Assessment of Nanomaterials

“…Lung organoids are already used for different research questions regarding NM toxicity. Readouts including reactive oxygen species (ROS) production, epithelial cell differentiation and regeneration, NP internalization or surfactant production can be assessed easily, and help to elucidate the mechanisms underlying disease progression in the lung after NP exposure [ 66 , 67 , 68 ]. Toxicity testing in organoids is not yet used often, but these examples already show the numerous opportunities with 3D lung cultures.…”

“…However, one difficulty still is to imitate the inhalation of NMs. For example, in Yu et al 2022 [ 68 ], the particles to be tested are mixed into the culture medium, which is without a doubt a convenient and high throughput suitable approach for NM exposure, but leads to similar problems regarding the cell delivered dose and the particle–cell interaction as a conventional 2D submerged cell culture does. Nevertheless, 3D organoids are able to respond to stimuli and can recapitulate epithelial cell responses more accurately than 2D culture [ 69 ].…”

The Effects and Pathogenesis of PM2.5 and Its Components on Chronic Obstructive Pulmonary Disease

“… 94 After being exposed to PM2.5, it is observed that there are fewer multilamellar bodies in the Alveolar epithelial type II; cell (AT2) increases mitochondrial swelling, collagen deposition, and pulmonary inflammation. 95 In addition, it can be observed that the dysregulated AT2 cells into AT1 cells in the PM2.5-induced COPD mouse model 96 damage cellular repair mechanisms. Even worse, it has been shown that inflamed bronchial epithelial cells caused by air pollution particles trigger apoptosis, 97 particularly when PM2.5 is injected into those inflamed by cigarettes.…”