System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Research Support, Non-U.S. Gov't Ppublish 29 citations

PubMed: 34524912 DOI: 10.1152/ajplung.00574.2020

A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF.

Am J Physiol Lung Cell Mol Physiol 321(5):L859-L871

Authors: Michael Schuliga, Amama Kanwal, Jane Read, Kaj E C Blokland, Janette K Burgess, Cecilia M Prêle, Steven E Mutsaers, Christopher Grainge, Claire Thomson, Allen James, Nathan W Bartlett, Darryl A Knight

Affiliations

  • School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
  • Priority Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia. Priority Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Department of Pathology and Medical Biology, Groningen Research Institute of Asthma and COPD and KOLFF Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Institute for Respiratory Health, University of Western Australia, Nedlands, Western Australia, Australia.
  • Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedlands, Western Australia, Australia.
  • School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
  • John Hunter Hospital, Newcastle, New South Wales, Australia.
  • St Vincent's Hospital, Sydney, New South Wales, Australia.
  • Providence Health Care Research Institute, Vancouver, British Columbia, Canada.

Abstract

Alveolar epithelial cell (AEC) senescence is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). 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, = 5) exhibited higher baseline senescence than AECs from control donors (Ctrl-AECs, = 5-7), as assessed by increased nuclear histone 2AXγ 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.

MeSH

Cellular Senescence, Pharmaceutical Preparations, Dna, Mitochondrial, Therapeutics, Alveolar Epithelial Cells, Rna, Small Interfering, Lung, Tissues, Etoposide, Dna Damage, Epithelial Cell Adhesion Molecule

Cited by