Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer
Open accessAbstract
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.
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COPD patients have defects in DNA repair, as documented by very low expression of the double-stranded repair protein Ku86.
“Contrary to normal smokers, COPD patients have defects in DNA repair, as documented by very low expression of the double-stranded repair protein Ku86 (Caramori et al. 2011).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Caramori et al. 2011
8-hydroxy-Gua is increased in the peripheral lungs of patients with COPD, confirming the occurrence of oxidative stress in the lungs.
“A well-known biomarker of oxidative DNA damage, 8-hydroxy-Gua, is increased in the peripheral lungs of patients with COPD, confirming thus the occurrence of oxidative stress in the lungs (Caramori et al. 2011).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Caramori et al. 2011
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- Authors
- Caramori, G., Adcock, I. M., Casolari, P., Ito, K., Jazrawi, E., Tsaprouni, L., Villetti, G., Civelli, M., Carnini, C., Chung, K. F., Barnes, P. J., & Papi, A.
- Affiliations
- University of Ferrara (IT)
- Imperial College London (GB)
- Chiesi (Italy) (IT)
- Corresponding author
- Caramori, G.
- Venue
- Thorax
- Publisher
- BMJ
- Published
- 2011-04-02
- Volume
- 66
- Issue
- 6
- Pages
- 521-527
- ISSN
- 0040-6376 (ISSN-L)
- OpenAlex
- W2111591597
- Cited by
- 187
- References
- 30
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 14 · 2022: 17 · 2021: 8 · 2020: 17 · 2019: 14 · 2018: 9 · 2017: 20 · 2016: 12 · 2015: 9 · 2014: 5 · 2013: 21 · 2012: 7
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Thorax (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, other-oa)
- BCU Open Access Repository (Birmingham City University) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0508-10212)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- chronic obstructive pulmonary disease, DNA damage, DNA repair, oxidative stress, Ku80, DNA-dependent protein kinase, lung cancer risk, smoking, abasic sites, bronchial epithelial cells, antioxidants, Ku70, DNA-PKcs
- MeSH terms
- Ku Autoantigen, Adult, Aged, Animals, Bronchi, Cells, Cultured, Disease Models, Animal, DNA Damage, DNA Repair, DNA-Binding Proteins, Epithelial Cells, Female, Humans, Hydrogen Peroxide, Lung Neoplasms, Male, Mice, Inbred C57BL, Middle Aged, Smoking, Oxidative Stress, Pulmonary Disease, Chronic Obstructive, Antigens, Nuclear, Mice
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