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Mitochondrial dysfunction including release of mitochondrial DNA (mtDNA) is a feature of senescence, which led us to investigate the role of the DNA-sensing guanine monophosphate-adenine monophosphate (GMP-AMP) synthase (cGAS) in IPF, with a focus on AEC senescence. cGAS expression in fibrotic tissue from lungs of patients with IPF was detected within cells immunoreactive for epithelial cell adhesion molecule (EpCAM) and p21, epithelial and senescence markers, respectively. Submerged primary cultures of AECs isolated from lung tissue of patients with IPF (IPF-AECs, n = 5) exhibited higher baseline senescence than AECs from control donors (Ctrl-AECs, n = 5\u20137), as assessed by increased nuclear histone 2AX\u03b3 phosphorylation, p21 mRNA, and expression of senescence-associated secretory phenotype (SASP) cytokines. Pharmacological cGAS inhibition using RU.521 diminished IPF-AEC senescence in culture and attenuated induction of Ctrl-AEC senescence following etoposide-induced DNA damage. Short interfering RNA (siRNA) knockdown of cGAS also attenuated etoposide-induced senescence of the AEC line, A549. Higher levels of mtDNA were detected in the cytosol and culture supernatants of primary IPF- and etoposide-treated Ctrl-AECs when compared with Ctrl-AECs at baseline. Furthermore, ectopic mtDNA augmented cGAS-dependent senescence of Ctrl-AECs, whereas DNAse I treatment diminished IPF-AEC senescence. This study provides evidence that a self-DNA-driven, cGAS-dependent response augments AEC senescence, identifying cGAS as a potential therapeutic target for IPF.<\/jats:p>","DOI":"10.1152\/ajplung.00574.2020","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T14:14:01Z","timestamp":1631715241000},"page":"L859-L871","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":54,"title":["A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF"],"prefix":"10.1152","volume":"321","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-5028","authenticated-orcid":true,"given":"Michael","family":"Schuliga","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia"},{"name":"Priority Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amama","family":"Kanwal","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia"},{"name":"Priority Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Read","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia"},{"name":"Priority Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-6359","authenticated-orcid":true,"given":"Kaj E. 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