DNA damage as a molecular link in the pathogenesis of COPD in smokers

Abstract

In this study, we investigated whether DNA double-strand breaks (DSBs) contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD).We immunofluorescence-stained lung tissue samples obtained from COPD patients, asymptomatic smokers and nonsmokers for markers of DSBs.The numbers of DSB foci (phosphorylated histone 2AX (cH2AX), phosphorylated ATM (ataxia telangiectasia mutated) substrate and phosphorylated p53-binding protein-1 foci) per cell in alveolar type I and II cells and endothelial cells were higher in the COPD patients than in the asymptomatic smokers and nonsmokers. The lung tissue in which type II cells contained higher numbers of cH2AX foci per cell had higher percentages of type II cells that expressed p16 INK4a(p16), phosphorylated nuclear factor (NF)-kB and interleukin (IL)-6, and of alveolar wall cells that expressed active caspase-3. The type II cells that contained higher numbers of cH2AX foci per cell had higher rates of expression of p16, phosphorylated NF-kB, and IL-6. Half of the alveolar wall cells that expressed active-caspase-3 contained cH2AX foci. Type II cells that stained positive for 8-hydroxy-2-deoxyguanosine contained a higher number of cH2AX foci per cell than the type II cells that stained negative.In conclusion, DSBs, at least in part caused by oxidative stress, appear to contribute to the pathogenesis of COPD by inducing apoptosis, cell senescence and pro-inflammatory responses.

The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD

“…Many investigators, including our own group, have reported the occurrence of DNA damage (including DNA oxidation and methylation, microsatellite DNA instability, loss of heterozygosity, and DNA doublestrand breaks) in the lung tissue of COPD patients [32][33][34][35][36][37][38]. DNA breaks have also been observed in peripheral blood lymphocytes [40,43].…”

“…Our recent studies using human lung tissue have revealed that: 1) ROS-mediated DNA double-strand breaks not observed in control smokers can be detected in the lung tissues of COPD patients, and 2) DNA double-strand breaks not only induce apoptosis and cell senescence, but also chronic inflammation via NF-kB-dependent pro-inflammatory cytokine production by senescent cells (SASP) [38,43,45]. Similarly, AMSELLEM et al [46] showed that senescent pulmonary vascular endothelial cells produce phlogogenic substances, such as IL-6, IL-8, MCP-1 and soluble intercellular adhesion molecule-1, in COPD patients.…”

“…In COPD, DNA damage may arise from the ROS or RNS released by inflammatory cells as well as the ROS present in tobacco smoke [31]. In fact, accumulating evidence suggests the occurrence of DNA damage in COPD [32][33][34][35][36][37][38][39][40][41][42].…”

Genomic instability in chronic airway inflammatory diseases

“…[82] In certain conditions, DNA damage triggers airway inflammation, and therefore causes COPD or asthma, while on the other hand, chronic inflammation may also enhance the levels of DNA damage. Currently, anti-inflammatory treatment is still a major strategy to manage airway inflammatory diseases.…”

“…By immunofluorescence staining of these particular proteins, researchers found that alveolar type I, type II cells, and endothelial cells in patients with COPD showed higher levels of DDR at DSBs than those found in asymptomatic smokers and non-smokers. [25] Somatic DNA alterations Microsatellite DNA instability (MSI) has been correlated with a high somatic mutation rate and is associated with deficiency of DNA mismatch repair. [26,27] It was reported in 1999 that MSI was found exclusively in the sputum cells of smokers with COPD, which indicated that genetic alteration might increase susceptibility to COPD.…”