Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer

Caramori, Gaetano and Adcock, Ian M and Casolari, Paolo and Ito, Kazuhiro and Jazrawi, Elen and Tsaprouni, Loukia and Villetti, Gino and Civelli, Maurizio and Carnini, Chiara and Chung, Kian Fan and Barnes, Peter J and Papi, Alberto (2011) Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax, 66 (6). pp. 521-527. ISSN 1468-3296

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Official URL: http://thorax.bmj.com/content/66/6/521

Abstract

BACKGROUND

Chronic 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.

OBJECTIVES

To 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.

METHODS

Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.

RESULTS

8-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.

CONCLUSIONS

Ineffective 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.

Item Type:

Article

Identification Number:

https://doi.org/10.1136/thx.2010.156448

Dates: