DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease

Jodie Birch, Rhys K. Anderson, Clara Correia-Melo, Diana Jurk, Graeme Hewitt, Francisco Madeira Marques, Nicola J. Green, Elizabeth Moisey, Mark A. Birrell, Maria G. Belvisi, Fiona Black, John J. Taylor, Andrew J. Fisher, Anthony De Soyza, João F. Passos

Research output: Contribution to journalArticle

52 Scopus citations

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 _-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, telomereassociated 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 lategeneration 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.

Original languageEnglish (US)
Pages (from-to)L1124-L1137
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number10
DOIs
StatePublished - Jan 1 2015

Keywords

  • Airway epithelial cells
  • Cigarette smoke
  • Senescence

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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    Birch, J., Anderson, R. K., Correia-Melo, C., Jurk, D., Hewitt, G., Madeira Marques, F., Green, N. J., Moisey, E., Birrell, M. A., Belvisi, M. G., Black, F., Taylor, J. J., Fisher, A. J., De Soyza, A., & Passos, J. F. (2015). DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. American Journal of Physiology - Lung Cellular and Molecular Physiology, 309(10), L1124-L1137. https://doi.org/10.1152/ajplung.00293.2015