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.

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

“…Another senescence marker, the cell cycle inhibitor p16, was found to be increased in total lung tissue, alveolar cells, airway epithelial cells, smooth muscle cells, endothelial cells and fibroblasts of COPD patients [75,76,[84][85][86]116]. Similarly, the presence of p21, another cell cycle inhibitor, was increased in total lung tissue, alveolar cells, smooth muscle cells, endothelial cells and leukocytes of COPD patients [79,80,[84][85][86].…”

“…Moreover, the percentages of p16-and p21-positive cells were negatively correlated with FEV1 % pred in alveolar type II and endothelial cells [86]. Levels of IL-6 and IL-8, two important cytokines that are secreted by senescent cells as part of the senescence-associated secretory phenotype, were increased in total lung tissue, alveolar cells, smooth muscle cells and endothelial cells of COPD patients as well as in CSE-treated fibroblasts [75,76,84,85]. Although these cytokines can also be the result of ongoing inflammation in COPD, these observations cannot be directly related to an increase in cellular senescence.…”

“…The DNA damage marker gamma-H2A histone family member X (γ-H2A.X) has been found to be increased in alveolar walls, including type I and type II epithelial cells and endothelial cells [75], as well as in small airways of COPD patients compared to controls [75,76]. Another study, however, showed no differences in small airways in COPD versus control [77].…”

“…Smoke exposure increases γ-H2A.X levels in experimental animal models, and cigarette smoke extract (CSE) treatment increases γ-H2A.X levels in bronchial epithelial cells and fibroblasts in vitro [76,78,79], suggesting an important role for oxidative stress. In addition, the anti-ageing protein sirtuin 6 (SIRT6) is considered to be protective against DNA damage and senescence.…”

“…The percentage of senescence-associated β-galactosidase-positive cells has been found to be increased in multiple cell types in COPD patients, including airway epithelial cells, smooth muscle cells, endothelial cells and fibroblasts, as well as in CSE-treated alveolar and bronchial epithelial cells [76,78,79,84,85,115,116]. Another senescence marker, the cell cycle inhibitor p16, was found to be increased in total lung tissue, alveolar cells, airway epithelial cells, smooth muscle cells, endothelial cells and fibroblasts of COPD patients [75,76,[84][85][86]116].…”