title: Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer.
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.
  
  
  OBJECTIVE
  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.
authors: Centro di Ricerca su Asma e BPCO, University of Ferrara, Via Savonarola, 9, Ferrara 44100, Italy. gaetano.caramori@unife.it
authors: Gaetano
authors: G
authors: Caramori
authors: Ian M
authors: IM
authors: Adcock
authors: Paolo
authors: P
authors: Casolari
authors: Kazuhiro
authors: K
authors: Ito
authors: Elen
authors: E
authors: Jazrawi
authors: Loukia
authors: L
authors: Tsaprouni
authors: Gino
authors: G
authors: Villetti
authors: Maurizio
authors: M
authors: Civelli
authors: Chiara
authors: C
authors: Carnini
authors: Kian Fan
authors: KF
authors: Chung
authors: Peter J
authors: PJ
authors: Barnes
authors: Alberto
authors: A
authors: Papi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000072200:Ku Autoantigen; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D006861:Hydrogen Peroxide; C000606512:Xrcc5 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen