title: DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease.
abstract: Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD.
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom; Lung Immunobiology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Jodie
authors.initials: J
authors.lastname: Birch
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom;
authors.forename: Rhys K
authors.initials: RK
authors.lastname: Anderson
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom;
authors.forename: Clara
authors.initials: C
authors.lastname: Correia-Melo
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom;
authors.forename: Diana
authors.initials: D
authors.lastname: Jurk
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom;
authors.forename: Graeme
authors.initials: G
authors.lastname: Hewitt
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom;
authors.forename: Francisco Madeira
authors.initials: FM
authors.lastname: Marques
authors.affiliation: Lung Immunobiology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Green
authors.affiliation: Lung Immunobiology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moisey
authors.affiliation: Respiratory Pharmacology, Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.affiliation: Respiratory Pharmacology, Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; and.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
authors.affiliation: Department of Pathology, Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Black
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: John J
authors.initials: JJ
authors.lastname: Taylor
authors.affiliation: Lung Immunobiology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fisher
authors.affiliation: Lung Immunobiology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Anthony
authors.initials: A
authors.lastname: De Soyza
authors.affiliation: Newcastle University Institute for Ageing, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, United Kingdom; joao.passos@newcastle.ac.uk.
authors.forename: João F
authors.initials: JF
authors.lastname: Passos
mesh_terms: D000368:Aged; D000375:Aging; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D020545:Respiratory Mucosa / Q000473:pathology; D012907:Smoking / Q000009:adverse effects; D016615:Telomere / Q000235:genetics*
keywords: airway epithelial cells; cigarette smoke; senescence