Chest
Volume 141, Issue 5, May 2012, Pages 1243-1250
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Original Research
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Oxidative DNA Damage and Somatic Mutations: A Link to the Molecular Pathogenesis of Chronic Inflammatory Airway Diseases

https://doi.org/10.1378/chest.11-1653Get rights and content

Background

Acquired somatic mutations induced by oxidative stress may contribute to the molecular pathogenesis of chronic inflammatory airway diseases. The objective of this study was to assess the intensity of oxidative DNA damage and the presence of microsatellite DNA instability (MSI), a marker of acquired somatic mutations, in patients with COPD, patients with noncystic fibrosis bronchiectasis, and control subjects.

Methods

Induced sputum and peripheral blood from 97 subjects were analyzed; 36 patients with COPD, 36 patients with bronchiectasis, 15 smokers without COPD, and 10 healthy control subjects. DNA was extracted and analyzed for MSI. 8-hydroxy-2′-deoxyguanosine (8-OHdG), a specific marker of oxidant-induced DNA damage, was measured in serum and sputum supernatants.

Results

None of the patients with bronchiectasis or control subjects (non-COPD smokers, healthy subjects) exhibited any genetic alteration. In contrast, MSI was found in 38% of COPD specimens. Sputum 8-OHdG was statistically significantly increased in COPD when compared with subjects with bronchiectasis (P = .0002), smokers without COPD (P = .0056), and healthy subjects (P = .0003). Sputum 8-OHdG in MSI-positive patients with COPD differed significantly from that of MSI-negative patients with COPD (P = .04) and smokers without COPD (P = .008), but was not statistically different (P = .07) among MSI-negative patients with COPD and smokers without COPD. Serum 8-OHdG was significantly increased in MSI-positive compared with MSI-negative patients with COPD (P = .001), but was not statistically significant in smokers without COPD (P = .09). Serum 8-OHdG was increased in smokers without COPD compared with MSI-negative patients with COPD (P = .009).

Conclusions

There is a clear disparity in COPD regarding oxidant-induced DNA damage and somatic mutations. This may reflect a difference in the oxidative stress per se or a deficient antioxidant and/or repair capacity in the lungs of patients with COPD.

Section snippets

Subjects

Informed consent was obtained from all subjects, and the protocol was approved by the medical ethics committee of the University Hospital of Heraklion, Crete, Greece (approval number 11980/20/10/2009). A total of 97 subjects were studied: 36 patients with COPD, 36 patients with bronchiectasis (non-COPD), 15 smokers without COPD, and 10 healthy subjects (nonsmokers). Patients were allocated into four groups: the first group consisted of 36 patients with GOLD (Global Initiative for Chronic

Results

COPD and bronchiectasis groups of patients were matched for age and smoking exposure but differed statistically in the parameters of lung function (FEV1 [% predicted], FVC [% predicted], and FEV1/FVC). Patients with ronchiectasis, smokers without COPD, and healthy subjects had normal lung function; thus, they were statistically significant different from patients with COPD (Table 1).

Discussion

We report higher levels of oxidant-induced DNA damage, as revealed by 8-OHdG marker, and increased frequency of acquired somatic mutations, as revealed by MSI, in patients with COPD when compared with smokers without COPD, patients with bronchiectasis, and healthy subjects. Our results could provide another link in the molecular pathogenesis of COPD, with the 8-OHdG levels reflecting the ongoing oxidative DNA damage and the MSI reflecting the inefficient DNA repair capacity of the organism.

To

Acknowledgments

Author contributions: Drs Tzortzaki, Dimakou, Neofytou, and Siafakas had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Tzortzaki: contributed to the study concept and design, analyzed and interpreted the data, drafted the manuscript, critically revised the manuscript for important intellectual content, and contributed to the statistical analysis.

Dr Dimakou: contributed to the study concept and design, acquired the

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  • Cited by (0)

    Drs Dimakou and Neofytou contributed equally to this study.

    Funding/Support: The authors have reported to CHEST that no funding was received for this study.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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