Mengyu Li, Yu Wang, Zhiqiang Hu, Shiqian Huang, Pu Chen, Lin Chen, Jing Wu, Zhouyang Wu, Shanglong Yao, Yiyi Yang
{"title":"PTEN-mediated senescence of lung epithelial cells drives ventilator-induced pulmonary fibrosis.","authors":"Mengyu Li, Yu Wang, Zhiqiang Hu, Shiqian Huang, Pu Chen, Lin Chen, Jing Wu, Zhouyang Wu, Shanglong Yao, Yiyi Yang","doi":"10.7150/thno.117523","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>Mechanical ventilation (MV), a life-saving intervention for acute respiratory distress syndrome (ARDS), may exacerbate pulmonary fibrosis (PF) through unclear mechanisms. Although Phosphatase and Tensin homolog (PTEN) suppresses chronic PF, its role in MV-induced PF remains unknown. This study will determine whether PTEN mediates MV-PF via lung epithelial cell senescence. <b>Methods:</b> Human lung epithelial cells exposed to hydrochloric acid (HCl) and mechanical stretch (48 hours) and a murine \"two-hit\" (HCl+MV) model (14-day observation) were used. PTEN's role was assessed via siRNA (<i>in vitro</i>) and knockout (<i>in vivo</i>). Single-cell transcriptomics analyzed senescence-associated secretory phenotype (SASP) and pathway enrichment. RG7388 (MDM2-P53 inhibitor) was administered to PTEN knockout mice to evaluate P53-mediated senescence. <b>Results:</b> HCl+MV induced epithelial-mesenchymal transition (EMT) and fibrosis <i>in vitro</i> and <i>in vivo</i>. PTEN knockout or knockdown attenuated these effects. Single-cell profiling indicated PTEN's role in EMT and fibrosis via cell senescence pathways, particularly in epithelial cells exhibiting imbalances in the SASP scores. Furthermore, our experiments confirmed that senescence activation during fibrosis was reversed by PTEN inhibition. RG7388 treatment in PTEN knockout mice implicated P53-mediated senescence in PTEN's regulatory role. <b>Conclusions:</b> Our study demonstrates that PTEN plays a pivotal role in MV-PF, by mediating pulmonary epithelial cell senescence. Future studies may focus on developing strategies to modulate PTEN activity and cell senescence to prevent or treat this devastating disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8360-8376"},"PeriodicalIF":13.3000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374584/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.117523","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Rationale: Mechanical ventilation (MV), a life-saving intervention for acute respiratory distress syndrome (ARDS), may exacerbate pulmonary fibrosis (PF) through unclear mechanisms. Although Phosphatase and Tensin homolog (PTEN) suppresses chronic PF, its role in MV-induced PF remains unknown. This study will determine whether PTEN mediates MV-PF via lung epithelial cell senescence. Methods: Human lung epithelial cells exposed to hydrochloric acid (HCl) and mechanical stretch (48 hours) and a murine "two-hit" (HCl+MV) model (14-day observation) were used. PTEN's role was assessed via siRNA (in vitro) and knockout (in vivo). Single-cell transcriptomics analyzed senescence-associated secretory phenotype (SASP) and pathway enrichment. RG7388 (MDM2-P53 inhibitor) was administered to PTEN knockout mice to evaluate P53-mediated senescence. Results: HCl+MV induced epithelial-mesenchymal transition (EMT) and fibrosis in vitro and in vivo. PTEN knockout or knockdown attenuated these effects. Single-cell profiling indicated PTEN's role in EMT and fibrosis via cell senescence pathways, particularly in epithelial cells exhibiting imbalances in the SASP scores. Furthermore, our experiments confirmed that senescence activation during fibrosis was reversed by PTEN inhibition. RG7388 treatment in PTEN knockout mice implicated P53-mediated senescence in PTEN's regulatory role. Conclusions: Our study demonstrates that PTEN plays a pivotal role in MV-PF, by mediating pulmonary epithelial cell senescence. Future studies may focus on developing strategies to modulate PTEN activity and cell senescence to prevent or treat this devastating disease.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.