期刊
EXPERIMENTAL AND MOLECULAR MEDICINE
卷 54, 期 12, 页码 2162-2174出版社
SPRINGERNATURE
DOI: 10.1038/s12276-022-00901-1
关键词
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资金
- National Natural Science Foundation of China (NSFC) [82172150]
- Shanghai Science and Technology Development Funds [22YF1423300]
Recent clinical research has found that mechanical ventilation (MV) can lead to pulmonary fibrosis, known as mechanical ventilation-induced pulmonary fibrosis (MVPF). This study investigates the potential mechanism of MVPF using a mouse model and an alveolar epithelial cell cyclic strain model, revealing that the ASK1-ER stress pathway plays a crucial role in the release of fibrotic extracellular vesicles (EVs) from alveolar epithelial cells, which contribute to fibroblast activation and the initiation of pulmonary fibrosis during MV.
Recent clinical research has revealed that mechanical ventilation (MV) can initiate pulmonary fibrosis and induce mechanical ventilation-induced pulmonary fibrosis (MVPF). However, the underlying mechanism remains largely uncharacterized. Based on a mouse model of MVPF and an alveolar epithelial cell cyclic strain model, the present study explores the possible mechanism of MVPF. Single-cell RNA-sequencing and EV RNA-sequencing analysis revealed that MV promoted apoptosis signal-regulating kinase 1 (ASK1)-mediated endoplasmic reticulum (ER) stress pathway activation and extracellular vesicle (EV) release from alveolar epithelial cells. Furthermore, the ASK1-ER stress pathway was shown to mediate mechanical stretch (MS)- or MV-induced EV release and lung fibroblast activation in vivo and in vitro. These processes were suppressed by ER stress inhibitors or by silencing ASK1 with ASK1- short hairpin RNA (shRNA). In addition, MVPF was suppressed by inhibiting ASK1 and ER stress in vivo. Therefore, the present study demonstrates that ASK1-ER stress pathway-mediated fibrotic-EV release from alveolar epithelial cells contributes to fibroblast activation and the initiation of pulmonary fibrosis during MV. The inhibited release of EVs targeting the ASK1-ER stress pathway might be a promising treatment strategy for MVPF.
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