• Gaetano Caramori, Ian M Adcock, Paolo Casolari, Kazuhiro Ito, Elen Jazrawi, Loukia Tsaprouni, Gino Villetti, Maurizio Civelli, Chiara Carnini, Kian Fan Chung, Peter J Barnes, and Alberto Papi.
• Centro di Ricerca su Asma e BPCO, University of Ferrara, Via Savonarola, 9, Ferrara 44100, Italy. gaetano.caramori@unife.it
• Thorax. 2011 Jun 1; 66 (6): 521-7.

BackgroundChronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex.ObjectivesTo investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.MethodsProtein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.Results8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p < 0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p < 0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p < 0.012) and prevented by antioxidants. Oxidants reduced (p < 0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress.ConclusionsIneffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.

43 keywords...

hide…