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Lookup NU author(s): Ben Barksby, Rachel Burgoyne, Dr Lee BorthwickORCiD, Professor Andrew FisherORCiD
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© 2025 by the American Thoracic Society. Cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The mechanisms of senescence in the bronchial epithelium, however, remain largely unknown. In this study, we aimed to elucidate whether cellular senescence in COPD epithelial cells contributes to the pathogenesis of the disease and investigated the potential molecular mechanisms involved. Single-cell RNA sequencing was performed on well-differentiated primary bronchial epithelial cells from patients with COPD and healthy subjects. We evaluated the abundance and distribution of senescence markers in key epithelial differentiated subtypes and senescence-associated secretory phenotype involved in airway epithelial dysfunction. The effects of IFN-pathway inhibitors on cellular senescence were also investigated. There was increased expression of cellular senescence genes in the COPD cohort, which was predominantly in basal and club cells. Enhanced expression of cellular senescence markers, p16 and p21, was observed in COPD cultures, which was histologically confirmed in the lung tissue of patients with COPD. There was also a notable increase in IFN-b and IFN-g. Senescence-associated secretory phenotype productions were increased in COPD and were attenuated by JAK-STAT or cGAS-STING pathway inhibitors (baricitinib or C-176). These inhibitors also effectively suppressed expression of senescence markers. COPD bronchial epithelium displays a senescence-driven phenotype which is mediated by Type I/II IFNs. Inhibition of JAK-STAT or STING-cGAS IFN pathways may represent targets to alleviate cellular senescence and chronic inflammation in COPD.
Author(s): Guo-Parke H, Cappa O, Linden DA, Barksby BS, Burgoyne RA, Borthwick LA, Fisher AJ, Weldon S, Simpson DA, Taggart CC, Kidney JC
Publication type: Article
Publication status: Published
Journal: American Journal of Respiratory Cell and Molecular Biology
Year: 2025
Volume: 73
Issue: 6
Pages: 871-883
Print publication date: 01/12/2025
Online publication date: 20/06/2025
Acceptance date: 20/06/2025
ISSN (print): 1044-1549
ISSN (electronic): 1535-4989
Publisher: American Thoracic Society
URL: https://doi.org/10.1165/rcmb.2024-0453OC
DOI: 10.1165/rcmb.2024-0453OC
PubMed id: 40540688
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