Next Article in Journal / Special Issue
UBE4B: A Promising Regulatory Molecule in Neuronal Death and Survival
Previous Article in Journal
Changes in Molecular Characteristics of Cereal Carbohydrates after Processing and Digestion
Previous Article in Special Issue
Identification of Candidate Polymorphisms on Stress Oxidative and DNA Damage Repair Genes Related with Clinical Outcome in Breast Cancer Patients
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

DNA Damage Due to Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD)

1
Laboratory of Molecular and Cellular Pulmonology, Medical School, University of Crete, Crete 71110, Greece
2
Department of Thoracic Medicine, University Hospital of Heraklion, Crete 71110, Greece
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2012, 13(12), 16853-16864; https://doi.org/10.3390/ijms131216853
Submission received: 28 September 2012 / Revised: 31 October 2012 / Accepted: 19 November 2012 / Published: 10 December 2012
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases)

Abstract

:
According to the American Thorasic Society (ATS)/European Respiratory Society (ERS) Statement, chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease with a strong genetic component, characterized by airflow limitation that is not fully reversible, but is usually progressive and associated with an enhanced inflammatory response of the lung to noxious particles or gases. The main features of COPD are chronic inflammation of the airways and progressive destruction of lung parenchyma and alveolar structure. The pathogenesis of COPD is complex due to the interactions of several mechanisms, such as inflammation, proteolytic/antiproteolytic imbalance, oxidative stress, DNA damage, apoptosis, enhanced senescence of the structural cells and defective repair processes. This review focuses on the effects of oxidative DNA damage and the consequent immune responses in COPD. In susceptible individuals, cigarette smoke injures the airway epithelium generating the release of endogenous intracellular molecules or danger-associated molecular patterns from stressed or dying cells. These signals are captured by antigen presenting cells and are transferred to the lymphoid tissue, generating an adaptive immune response and enhancing chronic inflammation.

Graphical Abstract

1. Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD)

The respiratory tract is in direct contact with the external environment. Considering its large surface area the lung is highly prone to injury since it is exposed to high concentrations of oxygen, pollutants, toxicants and cigarette smoke [13]. Host factors including genetic susceptibility, epigenetic changes, and oxidative stress contribute to COPD pathogenesis by amplifying inflammation induced by inhaled toxic substances and mainly cigarette smoke [48].
Cigarette smoke releases thousands of oxidants, free radicals and chemical compounds, including hydroxyl radicals (−OH) and hydrogen peroxide (H2O2). Moreover, it recruits immune and inflammatory cells (e.g., alveolar macrophages, epithelial and endothelial cells, neutrophils, eosinophils, monocytes and lymphocytes) to the lungs aggravating the oxidant/antioxidant imbalance [2,3,9].
Oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, mitochondrial dysfunction, alveolar epithelial injury, remodeling of extracellular matrix, altered apoptosis and cellular DNA damage are considered effects of oxidative stress in the lung [1,10]. In addition, the kinase signaling pathways induced by oxidative stress, lead to chromatin modifications (histone methylation/demethylation and histone acetylation/deacetylation) in inflammation, senescence, and steroid resistance.
Although oxidative stress, under normal circumstances, is combated by multiple antioxidant and repair systems used for the replacement of damaged cells, nucleic acids, proteins and lipids, an imbalance between oxidants and antioxidants is present in the lungs of patients with COPD [1,9,11].

2. Oxidative DNA Damage

Oxidative stress on cells most frequently targets the DNA. Evidence show that the continuous oxidative damage of the DNA is involved in the pathophysiology of various diseases and conditions such as cancer, atherosclerosis, neurodegenerative disorders, chronic lung diseases, aging [12].
The distribution of oxidative damage in the genome depends on the varying susceptibility of sequences to oxidative attack, and the preferential targeting of repair processes. Non-coding DNA (microsatellite sequences-MS, telomeres, promoters and sites of methylation), is particularly prone to oxidative damage due to its base composition. Although all DNA bases are susceptible to damage, guanine is most prone to oxidative modification. 8-Hydroxyguanine (8-OH-Gua), and its 2′-deoxynucleoside equivalent, 8-hydroxy-2′-deoxyguanosine (8-OHdG), are the most common byproducts. 8-OH-dG is excreted during the repair of damaged DNA in vivo, by exonucleases considering it as a marker of oxidant-induced DNA damage [13,14]. This phenomenon has notable biological consequences, since repair processes directed to non-coding regions are slower and less efficient [9,11,15].
Recent studies have shown that the lung tissue from COPD patients displays oxidative DNA damage [14,16]. The expression of 8-OHdG is significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers while the number of DNA damage and repair sites was increased in smokers compared with non-smokers and patients with COPD, implying the existence of a DNA damage/repair imbalance in COPD [14,16]. Others, using immunohistochemistry, showed that following cigarette smoke exposure, there were increased signals of 8-OHdG in the bronchiolar epithelial cells and the alveolar epithelial cells, particularly type II cells, in animal models [17,18]. Similarly, previous studies of our group have shown that 8-OHdG levels were statistically significantly increased in COPD patients compared to non-COPD smokers and non-smokers and especially in a COPD subgroup with microsatellite instability (MSI) [7].
Other studies mainly focused on determining whether the oxidative DNA damage was randomly distributed or localized in specific sequences in either the nuclear or mitochondrial genomes. It has been shown that oxidative DNA damage in COPD lungs was prominent in the hypoxic response element (HRE) of the Vascular Endothelial Growth Factor (VEGF) promoter, which could contribute to transcriptional deregulation and cell fate decisions in COPD [19].
The oxidative damage in DNA by cigarette smoke is either caused directly, as already discussed, or through the generation of reactive oxygen species (ROS) [20]. ROS oxidatively damage nucleic acids, requiring multiple repair mechanisms, such as base excision pathway components 8-oxoguanine-DNA glycosylase (OGG1), endonuclease III homologue 1 (NTH1), and single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), as well as the nucleic acid-binding protein, Y-box binding protein 1 (YB1). Studies have shown that ROS-dependent, cigarette smoke-induced nucleic-acid oxidation in alveolar fibroblasts, is involved in the pathogenesis of emphysema [21].
In addition, DNA methylation is shown to regulate the expression of pro-inflammatory genes during the development of COPD. DNA methylation of the promoters of pro-inflammatory genes has been observed both in airway epithelial cells and alveolar macrophages. The DNA methylation status in COPD shows changes similar to that observed in cancer tissues, with hypermethylation of specific promoters and loss of global DNA methylation mainly due to a demethylation in repetitive elements [2225].
Finally, since aging is characterized by telomeres shortening, the relationship between telomere length and COPD is under investigation. The observation that telomere length in circulating leukocytes of COPD patients are shorter than those of controls, is likely due to the increased systemic oxidative stress, in line with what has been observed in other chronic inflammatory disorders associated to telomere shortening [24,2629].

3. DNA Repair Mechanisms

Direct repair, base excision repair, nucleotide excision repair, double-strand break repair (DSB), and cross-link repair are defined in [30]. The maintenance of chromosomal integrity is dependent on the efficient repair of DNA DSBs [3133], since those caused by oxidative stress appear to contribute to the pathogenesis of COPD by inducing apoptosis, cell senescence and pro-inflammatory responses [34].
The inefficiency of DNA repair is a common finding in COPD. This could be due to heritable genetic polymorphisms that influence the efficiency of DNA repair mechanisms in both the bronchial epithelium and connective tissue [35,36]. Numerous studies have shown that cigarette smoke causes DNA damage and impaired DSB repair, which indeed is aggravated in patients with COPD/emphysema [14,18,19,21,34,37]. Combined COPD genetic studies have identified XRCC5 as an additional COPD susceptibility gene on chromosome 2q. XRCC5 is an ATP-dependent DNA helicase involved in DNA double-strand break (DSB) repair and immunoglobulin Variable, Diverse, and Joining [V(D)J] rearrangement, also known as Ku80 or Ku86. This has been implicated in the development of COPD and specifically in early-onset COPD, and also in animal models [3842].
Interestingly, women have a 10%–15% lower capacity for repairing tobacco induced DNA damage than men [43]. There is also evidence that the DNA repair mechanisms may play an important role in the epigenetic regulation of cell function by mediating DNA demethylation [44].
According to recent evidence, acetylation of histone H3 on lysine 56 AcH3K56 has a critical role in DNA damage and repair [45,46]. Histone deacetylase (HDACs) 2 posttranslational modifications play an important role in the regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response and cellular senescence [47]. Sirtuins also play a crucial role in deacetylating H3K56 in mammalian cells [46,48], suggesting that in diseases such as COPD, where there is a decrease in HDAC2 [49] and SIRT1 (NAD+-dependent protein/histone deacetylase) [5052] expression, the decreased protection against DNA breakage and repair can be explained together with the increase of somatic mutations. Specifically, the anti-aging SIRT1, that is reduced in lungs of COPD patients, seems to protect against emphysema through FOXO3 (Forkhead box O3)-mediated reduction of cellular senescence, independently of inflammation [53].
Finally, given the important role of mitochondria in the DNA damage and the antioxidant capacity of the human organism, we evaluated the inner mitochondrial membrane proteins (PHB1 and PHB2) in COPD patients [54]. Prohibitins (PHB1 and PHB2) interact with the Nicotinamide adenine dinucleotide hydrogen (NADH) dehydrogenase protein complex, which is essential for oxidoreductase activity within cells. Smoking, due to increased ROS production, damages the mitochondrial respiratory machinery [5557]. We demonstrated that PHB1 mRNA and protein levels decreased at a linear rate from non-smokers to non-COPD smokers to COPD patients, reflecting a reduced respiratory mitochondrial function, resulting in decreased anti-oxidant capacity, especially in the mitochondria of COPD patients [54].

4. DNA Damage—Somatic Mutations in the Microsatellite DNA

Several cellular responses are activated upon DNA damage that enable the cell to either eliminate or reverse the damage or to activate programmed cell death, presumably to eliminate cells with potentially catastrophic mutations. These somatic mutations are usually associated with oncogenes and inflammatory signaling pathways [7,30,58,59].
The oxidative DNA damage in the lung generally affects the base composition of the repeated sequences (microsatellite DNA) especially when coupled with DNA mismatch repair system (MMR) deficiency [11,15].
The microsatellite repeats are identical in the different cells of each individual, and unique. Their characteristics are that they are found scattered throughout the genome, are usually located outside or within coding sequences and are faithfully replicated in healthy cells ensuring that coding sequences remain within the appropriate reading frame [5,11,18]. Frame shift mutations in downstream genes are induced by insertion or deletion of one or more repeat units. They have been used as polymorphic markers used for genome mapping in many organisms, including humans [5,11,18]. The MMR system is important for the maintenance of microsatellite stability, as it is designed to correct single-base mismatches and small insertion/deletion loops that may occur during DNA replication [60]. The study of microsatellite DNA instability (MSI) in lung tissue samples offers an index of acquired mutations and is achieved with the use of microsatellite markers targeting specific chromosomal loci near or in genes that could be implicated in the pathogenesis of a disease [5,11,18].

5. Microsatellite DNA Instability in COPD

The induction of MSI by oxidants in COPD has significant biological relevance, given the association of MSI with chronic inflammation, where oxidant production would be enhanced [7].
Ever since the Microsatellite DNA Instability (MI) was established in benign lung diseases, such as COPD and asthma [58,61,62], comparative studies between COPD and asthma at the microsatellite DNA level, revealed that COPD patients had a higher frequency of somatic mutations when compared with asthmatics [63]. Those studies revealed genetic instability in COPD specific microsatellite sites adjacent to genes related to COPD pathogenesis (e.g., Surfactant A, Perforin, cluster of differentiation (CD8), Tumor necrosis factor (TNF)). What was important was to assess the relationship between COPD exacerbations and genetic instability, since the “frequent COPD exacerbator” exhibited the highest rates of genetic defects, implying that persistent inflammation and increased oxidative burden on cells during exacerbations, could lead to greater oxidative DNA damage when compared with stable COPD [64].
What was next to be explored was the identification of the susceptible sputum cell subpopulation to acquired somatic mutations. Studies from our group were focused on the lung epithelial barrier cells (LEBCs), which constitute the outer cellular layer of the bronchial tree and are exposed to numerous host and environmental insults [65]. The air–lung barrier system, the first line of defense according to numerous studies, is constantly affected by the burden of inhaled oxidants from cigarette smoking and the increased amount of reactive oxygen species generated by various inflammatory cells of the airways in COPD [1,2]. Using immuno-magnetic beads for sputum cell separation followed by flow cytometry and microsatellite DNA analysis, Samara et al. verified that somatic DNA alterations were exclusively exhibited in the lung epithelial barrier cells of COPD patients [65].

6. DNA Damage Due to Oxidative Stress in COPD: A Hypothesis

Based on current studies, we have already proposed a new hypothesis on the pathogenesis of COPD including the oxidative DNA damage of the lung epithelial barrier cells (LEBCs) in COPD [8].
In the initiation of COPD, cigarette smoking affects the air-lung barrier system and, especially, the epithelium via repeated oxidative stress leading to oxidative DNA damage [2,10,15]. The “danger hypothesis” of Matzinger, further explains how cigarette smoke and oxidative stress triggers the innate immune response. According to her theory, it is not only the presence of an external antigen (e.g., pathogens, toxins, smoke) that alerts the immune system to respond but also self-antigens (endogenous intracellular molecules or danger-associated molecular patterns from stressed or dying cells) [66]. These molecular patterns or self-antigens are being recognized by Toll-like receptors (TLRs), the sensors of the innate immune system [67].
Cigarette smoke contains more than 2000 xenobiotic compounds and 1014 free radicals that injure lung epithelial cells and cause the breakdown of connective tissue in smokers [68,69]. Epithelial cell injury products can act as ligands for TLRs, inducing epithelial cells to produce inflammation mediators. These mediators activate alveolar macrophages and neutrophils [70,71], which in turn secrete proteolytic enzymes and, together with reactive oxygen species, further damage lung tissue [72]. The polarised cells travel then to the draining lymph nodes and present danger signals to the naive T-lymphocytes, inducing a proliferation of CD8+ cytotoxic T-lymphocytes. The CD8+ T-cells, in turn, migrate to the sites of the initial insult, releasing perforin and granzymes and attack the altered LEBCs activating cell death cascades [4,8,73,74].
Oxidative stress, cell death and tissue trauma could release self-antigens, damage mitochondria, modify proteins and release truncated DNA from apoptotic cells [7577]. These products can be recognized by the adaptive immune system as foreign antigens, triggering an immune reaction. Similarly, in smokers, such antigens have been shown to be released as a result of necrosis and apoptosis of epithelial and endothelial cells and extracellular-matrix injury [7681]. On the other hand, Toll-like Receptors (TLRs) link innate and adaptive immunity, enhancing the pathogenic potential of those antigens [8285].
Besides, the damaged DNA of LEBCs due to oxidative stress, leads to increased expression of 8-OHdG, further generation of ROS, decreased DNA auto-repair ability and finally somatic mutations [7,14,15,17,18,20,30,36,65]. Evidently, after smoking cessation, oxidative stress and somatic mutations persist in a number of COPD patients, perpetuating pulmonary inflammation.
The DNA damage response (DDR), the cellular response that allows DNA damage detection, signaling and repair is stimulated at any place and any time, where and when DNA lesions occur [10,86,87]. Oxidative DNA damage, DSBs and HDAC2 posttranslational modifications have recently been shown to induce DDR, which in turn causes chronic inflammation in COPD as a result of profound cellular changes to the senescence-associated secretory phenotype (SASP). The SASP can disrupt normal tissue structures and function [34,47,88]. Senescence of alveolar epithelial cells limits cell proliferation causing increased production of pro-inflammatory cytokines, hence promoting inflammation. When alveolar epithelial cells reach the senescent stage, the lungs suffer both from impaired alveolar regeneration and exaggerated alveolar inflammation, thereby contributing to COPD pathogenesis [41,89,90].
As already discussed, the cells of COPD patients, in response to oxidative stress, present reduced HDAC2 activity which has been linked to increased acetylation of the antioxidant transcription factor Nuclear respiratory factor 2 (Nrf 2), impairing Nrf 2 activity, and to the upregulation of antioxidant enzymes [91]. Moreover, the impairment of Nrf2-mediated antioxidant defenses, along with epigenetic changes induced by ROS (histone modifications) and mitochondrial dysfunction, seems to prolong the oxidative stress in COPD [49,92,93].

7. Conclusion

In conclusion, oxidative DNA damage contributes to the molecular pathogenesis of COPD. Increased 8-OHdG expression and acquired somatic mutations in COPD are the result of the oxidative DNA damage and the inefficient DNA repair machinery. Moreover, since the SASP is largely a response to genomic or epigenomic damage, it may be a model for a cellular damage response that can propagate damage signals both within and among tissues. Since COPD is thought to be a degenerative disease of aging, it may be fueled by such damage signals. The varying efficiency of DNA repair across the genome may be viewed as analogous to inter-individual variation in repair efficiency, a potential determinant of disease susceptibility.

Supplementary Information

ijms-13-16853-s001.pdf

Acknowledgments

Supported by Competitive Research Grants (2008, 2011) of the “Hellenic Thoracic Society”.
  • Conflict of InterestThe authors declare no conflict of interest.

References

  1. Avery, S.V. Molecular targets of oxidative stress. Biochem. J 2011, 434, 201–210. [Google Scholar]
  2. Faux, S.P.; Tai, T.; Thorne, D.; Xu, Y.; Breheny, D.; Gaca, M. The role of oxidative stress in the biological responses of lung epithelial cells to cigarette smoke. Biomarkers 2009, 14, 90–96. [Google Scholar]
  3. Wistuba, II; Mao, L.; Gazdar, A.F. Smoking molecular damage in bronchial epithelium. Oncogene 2002, 21, 7298–7306. [Google Scholar]
  4. Brusselle, G.G.; Joos, G.F.; Bracke, K.R. New insights into the immunology of chronic obstructive pulmonary disease. Lancet 2011, 378, 1015–1026. [Google Scholar]
  5. Celli, B.R.; MacNee, W. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur. Respir. J 2004, 23, 932–946. [Google Scholar]
  6. Decramer, M.; Janssens, W.; Miravitlles, M. Chronic obstructive pulmonary disease. Lancet 2012, 379, 1341–1351. [Google Scholar]
  7. Tzortzaki, E.G.; Dimakou, K.; Neofytou, E.; Tsikritsaki, K.; Samara, K.; Avgousti, M.; Amargianitakis, V.; Gousiou, A.; Menikou, S.; Siafakas, N.M. Oxidative DNA damage and somatic mutations: A link to the molecular pathogenesis of chronic inflammatory airway diseases. Chest 2012, 141, 1243–1250. [Google Scholar]
  8. Tzortzaki, E.G.; Siafakas, N.M. A hypothesis for the initiation of COPD. Eur. Respir. J 2009, 34, 310–315. [Google Scholar]
  9. Chung, K.F.; Marwick, J.A. Molecular mechanisms of oxidative stress in airways and lungs with reference to asthma and chronic obstructive pulmonary disease. Ann. N. Y. Acad. Sci 2010, 1203, 85–91. [Google Scholar]
  10. Ciccia, A.; Elledge, S.J. The DNA damage response: Making it safe to play with knives. Mol. Cell 2010, 40, 179–204. [Google Scholar]
  11. Boyer, J.C.; Yamada, N.A.; Roques, C.N.; Hatch, S.B.; Riess, K.; Farber, R.A. Sequence dependent instability of mononucleotide microsatellites in cultured mismatch repair proficient and deficient mammalian cells. Hum. Mol. Genet 2002, 11, 707–713. [Google Scholar]
  12. Halliwell, B.; Gutteridge, J.M. Free Radicals in Biology and Medicine, 3rd ed; Oxford University Press: London, UK, 1999; pp. 50–70. [Google Scholar]
  13. Valavanidis, A.; Vlachogianni, T.; Fiotakis, C. 8-Hydroxy-2′-deoxyguanosine(8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev 2009, 27, 120–139. [Google Scholar]
  14. Caramori, G.; Adcock, I.M.; Casolari, P.; Ito, K.; Jazrawi, E.; Tsaprouni, L.; Villetti, G.; Civelli, M.; Carnini, C.; Chung, K.F.; et al. Unbalanced oxidant-induced DNA damage and repair in COPD: A link towards lung cancer. Thorax 2011, 66, 521–527. [Google Scholar]
  15. Anderson, G.P.; Bozinovski, S. Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol. Sci 2003, 24, 71–76. [Google Scholar]
  16. Igishi, T.; Hitsuda, Y.; Kato, K.; Sako, T.; Burioka, N.; Yasuda, K.; Sano, H.; Shigeoka, Y.; Nakanishi, H.; Shimizu, E. Elevated urinary 8-hydroxydeoxyguanosine, a biomarker of oxidative stress, and lack of association with antioxidant vitamins in chronic obstructive pulmonary disease. Respirology 2003, 8, 455–460. [Google Scholar]
  17. Aoshiba, K.; Koinuma, M.; Yokohori, N.; Nagai, A. Immunohistochemical evaluation of oxidative stress in murine lungs after cigarette smoke exposure. Inhal. Toxicol 2003, 15, 1029–1038. [Google Scholar]
  18. Deslee, G.; Woods, J.C.; Moore, C.; Conradi, S.H.; Gierada, D.S.; Atkinson, J.J.; Battaile, J.T.; Liu, L.; Patterson, G.A.; Adair-Kirk, T.L.; et al. Oxidative damage to nucleic acids in severe emphysema. Chest 2009, 135, 965–974. [Google Scholar]
  19. Pastukh, V.M.; Zhang, L.; Ruchko, M.V.; Gorodnya, O.; Bardwell, G.C.; Tuder, R.M.; Gillespie, M.N. Oxidative DNA damage in lung tissue from patients with COPD is clustered in functionally significant sequences. Int. J. Chron. Obstruct. Pulmon. Dis 2011, 6, 209–217. [Google Scholar]
  20. Babizhayev, M.A.; Yegorov, Y.E. Smoking and health: Association between telomere length and factors impacting on human disease, quality of life and life span in a large population-based cohort under the effect of smoking duration. Fundam. Clin. Pharmacol 2011, 25, 425–442. [Google Scholar]
  21. Deslee, G.; Adair-Kirk, T.L.; Betsuyaku, T.; Woods, J.C.; Moore, C.H.; Gierada, D.S.; Conradi, S.H.; Atkinson, J.J.; Toennies, H.M.; Battaile, J.T.; et al. Cigarette smoke induces nucleic-acid oxidation in lung fibroblasts. Am. J. Respir. Cell Mol. Biol 2010, 43, 576–584. [Google Scholar]
  22. Durham, A.; Chou, P.C.; Kirkham, P.; Adcock, I.M. Epigenetics in asthma and other inflammatory lung diseases. Epigenomics 2010, 2, 523–537. [Google Scholar]
  23. Liu, F.; Killian, J.K.; Yang, M.; Walker, R.L.; Hong, J.A.; Zhang, M.; Davis, S.; Zhang, Y.; Hussain, M.; Xi, S.; et al. Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene 2010, 29, 3650–3664. [Google Scholar]
  24. Provinciali, M.; Cardelli, M.; Marchegiani, F. Inflammation, chronic obstructive pulmonary disease and aging. Curr. Opin. Pulm. Med 2011, 17, 3–10. [Google Scholar]
  25. Yang, I.V.; Schwartz, D.A. Epigenetic control of gene expression in the lung. Am. J. Respir. Crit. Care Med 2011, 183, 1295–1301. [Google Scholar]
  26. Amsellem, V.; Gary-Bobo, G.; Marcos, E.; Maitre, B.; Chaar, V.; Validire, P.; Stern, J.B.; Noureddine, H.; Sapin, E.; Rideau, D.; et al. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med 2011, 184, 1358–1366. [Google Scholar]
  27. Babizhayev, M.A.; Savel’yeva, E.L.; Moskvina, S.N.; Yegorov, Y.E. Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior. Am. J. Ther 2011, 18, 209–226. [Google Scholar]
  28. Houben, J.M.; Mercken, E.M.; Ketelslegers, H.B.; Bast, A.; Wouters, E.F.; Hageman, G.J.; Schols, A.M. Telomere shortening in chronic obstructive pulmonary disease. Respir. Med 2009, 103, 230–236. [Google Scholar]
  29. Savale, L.; Chaouat, A.; Bastuji-Garin, S.; Marcos, E.; Boyer, L.; Maitre, B.; Sarni, M.; Housset, B.; Weitzenblum, E.; Matrat, M.; et al. Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med 2009, 179, 566–571. [Google Scholar]
  30. Sancar, A.; Lindsey-Boltz, L.A.; Unsal-Kacmaz, K.; Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem 2004, 73, 39–85. [Google Scholar]
  31. Meek, K.; Dang, V.; Lees-Miller, S.P. DNA-PK: The means to justify the ends? Adv. Immunol 2008, 99, 33–58. [Google Scholar]
  32. Kovacs, K.; Erdelyi, K.; Hegedus, C.; Lakatos, P.; Regdon, Z.; Bai, P.; Hasko, G.; Szabo, E.; Virag, L. Poly(ADP-ribosyl)ation is a survival mechanism in cigarette smoke-induced and hydrogen peroxide-mediated cell death. Free Radic. Biol. Med 2012, 53, 1680–1688. [Google Scholar]
  33. Meek, K.; Gupta, S.; Ramsden, D.A.; Lees-Miller, S.P. The DNA-dependent protein kinase: The director at the end. Immunol. Rev 2004, 200, 132–141. [Google Scholar]
  34. Aoshiba, K.; Zhou, F.; Tsuji, T.; Nagai, A. DNA damage as a molecular link in the pathogenesis of COPD in smokers. Eur. Respir. J 2012, 39, 1368–1376. [Google Scholar]
  35. Brody, J.S.; Spira, A. State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer. Proc. Am. Thorac. Soc 2006, 3, 535–537. [Google Scholar]
  36. Caramori, G.; Papi, A. Pathogenic link between chronic obstructive pulmonary disease and squamous cell lung cancer. Expert Rev. Respir. Med 2007, 1, 171–175. [Google Scholar]
  37. Ceylan, E.; Kocyigit, A.; Gencer, M.; Aksoy, N.; Selek, S. Increased DNA damage in patients with chronic obstructive pulmonary disease who had once smoked or been exposed to biomass. Respir. Med 2006, 100, 1270–1276. [Google Scholar]
  38. Hersh, C.P.; Pillai, S.G.; Zhu, G.; Lomas, D.A.; Bakke, P.; Gulsvik, A.; DeMeo, D.L.; Klanderman, B.J.; Lazarus, R.; Litonjua, A.A.; et al. Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene. Am. J. Respir. Crit. Care Med 2010, 182, 605–613. [Google Scholar]
  39. Vogel, H.; Lim, D.S.; Karsenty, G.; Finegold, M.; Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl. Acad. Sci. USA 1999, 96, 10770–10775. [Google Scholar]
  40. Suga, T.; Kurabayashi, M.; Sando, Y.; Ohyama, Y.; Maeno, T.; Maeno, Y.; Aizawa, H.; Matsumura, Y.; Kuwaki, T.; Kuro, O.M.; et al. Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. Am. J. Respir. Cell Mol. Biol 2000, 22, 26–33. [Google Scholar]
  41. Karrasch, S.; Holz, O.; Jorres, R.A. Aging and induced senescence as factors in the pathogenesis of lung emphysema. Respir. Med 2008, 102, 1215–1230. [Google Scholar]
  42. Tuder, R.M. Aging and cigarette smoke: Fueling the fire. Am. J. Respir. Crit. Care Med 2006, 174, 490–491. [Google Scholar]
  43. Wei, Q.; Cheng, L.; Amos, C.I.; Wang, L.E.; Guo, Z.; Hong, W.K.; Spitz, M.R. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: A molecular epidemiologic study. J. Natl. Cancer Inst 2000, 92, 1764–1772. [Google Scholar]
  44. Gehring, M.; Reik, W.; Henikoff, S. DNA demethylation by DNA repair. Trends Genet 2009, 25, 82–90. [Google Scholar]
  45. Miller, K.M.; Tjeertes, J.V.; Coates, J.; Legube, G.; Polo, S.E.; Britton, S.; Jackson, S.P. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat. Struct. Mol. Biol 2010, 17, 1144–1151. [Google Scholar]
  46. Vempati, R.K.; Jayani, R.S.; Notani, D.; Sengupta, A.; Galande, S.; Haldar, D. P300-Mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals. J. Biol. Chem 2010, 285, 28553–28564. [Google Scholar]
  47. Yao, H.; Rahman, I. Role of histone deacetylase 2 in epigenetics and cellular senescence: Implications in lung inflammaging and COPD. Am. J. Physiol. Lung Cell Mol. Physiol. 2012. [Google Scholar] [CrossRef]
  48. Yuan, Z.; Zhang, X.; Sengupta, N.; Lane, W.S.; Seto, E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 2007, 27, 149–162. [Google Scholar]
  49. Ito, K.; Ito, M.; Elliott, W.M.; Cosio, B.; Caramori, G.; Kon, O.M.; Barczyk, A.; Hayashi, S.; Adcock, I.M.; Hogg, J.C.; Barnes, P.J. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med 2005, 352, 1967–1976. [Google Scholar]
  50. Rajendrasozhan, S.; Yang, S.R.; Kinnula, V.L.; Rahman, I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med 2008, 177, 861–870. [Google Scholar]
  51. Nakamaru, Y.; Vuppusetty, C.; Wada, H.; Milne, J.C.; Ito, M.; Rossios, C.; Elliot, M.; Hogg, J.; Kharitonov, S.; Goto, H.; et al. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 2009, 23, 2810–2819. [Google Scholar]
  52. Caito, S.; Hwang, J.W.; Chung, S.; Yao, H.; Sundar, I.K.; Rahman, I. PARP-1 inhibition does not restore oxidant-mediated reduction in SIRT1 activity. Biochem. Biophys. Res. Commun 2010, 392, 264–270. [Google Scholar]
  53. Yao, H.; Chung, S.; Hwang, J.W.; Rajendrasozhan, S.; Sundar, I.K.; Dean, D.A.; McBurney, M.W.; Guarente, L.; Gu, W.; Ronty, M.; et al. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J. Clin. Invest 2012, 122, 2032–2045. [Google Scholar]
  54. Soulitzis, N.; Neofytou, E.; Psarrou, M.; Anagnostis, A.; Tavernarakis, N.; Siafakas, N.; Tzortzaki, E.G. Downregulation of lung mitochondrial prohibitin in COPD. Respir. Med 2012, 106, 954–961. [Google Scholar]
  55. Ciencewicki, J.; Trivedi, S.; Kleeberger, S.R. Oxidants and the pathogenesis of lung diseases. J. Allergy Clin. Immunol 2008, 122, 456–470. [Google Scholar]
  56. Merkwirth, C.; Langer, T. Prohibitin function within mitochondria: Essential roles for cell proliferation and cristae morphogenesis. Biochim. Biophys. Acta 2009, 1793, 27–32. [Google Scholar]
  57. Theiss, A.L.; Sitaraman, S.V. The role and therapeutic potential of prohibitin in disease. Biochim. Biophys. Acta 2011, 1813, 1137–1143. [Google Scholar]
  58. Siafakas, N.M.; Tzortzaki, E.G.; Sourvinos, G.; Bouros, D.; Tzanakis, N.; Kafatos, A.; Spandidos, D. Microsatellite DNA instability in COPD. Chest 1999, 116, 47–51. [Google Scholar]
  59. Tzortzaki, E.G.; Tsoumakidou, M.; Makris, D.; Siafakas, N.M. Laboratory markers for COPD in “susceptible” smokers. Clin. Chim. Acta 2006, 364, 124–138. [Google Scholar]
  60. Iyer, L.M.; Babu, M.M.; Aravind, L. The HIRAN domain and recruitment of chromatin remodeling and repair activities to damaged DNA. Cell Cycle 2006, 5, 775–782. [Google Scholar]
  61. Paraskakis, E.; Sourvinos, G.; Passam, F.; Tzanakis, N.; Tzortzaki, E.G.; Zervou, M.; Spandidos, D.; Siafakas, N.M. Microsatellite DNA instability and loss of heterozygosity in bronchial asthma. Eur. Respir. J 2003, 22, 951–955. [Google Scholar]
  62. Spandidos, D.; Ergazaki, M.; Hatzistamou, J.; Kiaris, H.; Bouros, D.; Tzortzaki, E.; Siafakas, N. Microsatellite instability in patients with chronic obstructive pulmonary disease. Oncol. Rep 1996, 3, 489–491. [Google Scholar]
  63. Zervou, M.I.; Tzortzaki, E.G.; Makris, D.; Gaga, M.; Zervas, E.; Economidou, E.; Tsoumakidou, M.; Tzanakis, N.; Milic-Emili, J.; Siafakas, N.M. Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease. Eur. Respir. J 2006, 28, 472–478. [Google Scholar]
  64. Makris, D.; Tzanakis, N.; Damianaki, A.; Ntaoukakis, E.; Neofytou, E.; Zervou, M.; Siafakas, N.M.; Tzortzaki, E.G. Microsatellite DNA instability and COPD exacerbations. Eur. Respir. J 2008, 32, 612–618. [Google Scholar]
  65. Samara, K.D.; Tzortzaki, E.G.; Neofytou, E.; Karatzanis, A.D.; Lambiri, I.; Tzanakis, N.; Siafakas, N.M. Somatic DNA alterations in lung epithelial barrier cells in COPD patients. Pulm. Pharmacol. Ther 2010, 23, 208–214. [Google Scholar]
  66. Matzinger, P. The danger model: A renewed sense of self. Science 2002, 296, 301–305. [Google Scholar]
  67. Parker, L.C.; Prince, L.R.; Sabroe, I. Translational mini-review series on Toll-like receptors: Networks regulated by Toll-like receptors mediate innate and adaptive immunity. Clin. Exp. Immunol 2007, 147, 199–207. [Google Scholar]
  68. Schriver, E.E.; Davidson, J.M.; Sutcliffe, M.C.; Swindell, B.B.; Bernard, G.R. Comparison of elastin peptide concentrations in body fluids from healthy volunteers, smokers, and patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis 1992, 145, 762–766. [Google Scholar]
  69. Stone, P.J.; Gottlieb, D.J.; O’Connor, G.T.; Ciccolella, D.E.; Breuer, R.; Bryan-Rhadfi, J.; Shaw, H.A.; Franzblau, C.; Snider, G.L. Elastin and collagen degradation products in urine of smokers with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med 1995, 151, 952–959. [Google Scholar]
  70. Mio, T.; Romberger, D.J.; Thompson, A.B.; Robbins, R.A.; Heires, A.; Rennard, S.I. Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am. J. Respir. Crit. Care Med 1997, 155, 1770–1776. [Google Scholar]
  71. Mills, P.R.; Davies, R.J.; Devalia, J.L. Airway epithelial cells, cytokines, and pollutants. Am. J. Respir. Crit. Care Med 1999, 160, 38–43. [Google Scholar]
  72. Richards, G.A.; Theron, A.J.; Van der Merwe, C.A.; Anderson, R. Spirometric abnormalities in young smokers correlate with increased chemiluminescence responses of activated blood phagocytes. Am. Rev. Respir. Dis 1989, 139, 181–187. [Google Scholar]
  73. Cosio, M.G.; Saetta, M.; Agusti, A. Immunologic aspects of chronic obstructive pulmonary disease. N. Engl. J. Med 2009, 360, 2445–2454. [Google Scholar]
  74. Tsoumakidou, M.; Koutsopoulos, A.V.; Tzanakis, N.; Dambaki, K.; Tzortzaki, E.; Zakynthinos, S.; Jeffery, P.K.; Siafakas, N.M. Decreased small airway and alveolar CD83+ dendritic cells in COPD. Chest 2009, 136, 726–733. [Google Scholar]
  75. Krieg, A.M.; Vollmer, J. Toll-Like receptors 7, 8, and 9: Linking innate immunity to autoimmunity. Immunol. Rev 2007, 220, 251–269. [Google Scholar]
  76. Rao, T.; Richardson, B. Environmentally induced autoimmune diseases: potential mechanisms. Environ. Health Perspect 1999, 107, 737–742. [Google Scholar]
  77. Rose, N.R. The role of infection in the pathogenesis of autoimmune disease. Semin. Immunol 1998, 10, 5–13. [Google Scholar]
  78. Marrack, P.; Kappler, J.; Kotzin, B.L. Autoimmune disease: Why and where it occurs. Nat. Med 2001, 7, 899–905. [Google Scholar]
  79. Ermann, J.; Fathman, C.G. Autoimmune diseases: Genes, bugs and failed regulation. Nat. Immunol 2001, 2, 759–761. [Google Scholar]
  80. Steinman, L. State of the art. Four easy pieces: Interconnections between tissue injury, intermediary metabolism, autoimmunity, and chronic degeneration. Proc. Am. Thorac. Soc 2006, 3, 484–486. [Google Scholar]
  81. Rose, N.; Afanasyeva, M. Autoimmunity: Busting the atherosclerotic plaque. Nat. Med 2003, 9, 641–642. [Google Scholar]
  82. Schaefer, L.; Babelova, A.; Kiss, E.; Hausser, H.J.; Baliova, M.; Krzyzankova, M.; Marsche, G.; Young, M.F.; Mihalik, D.; Gotte, M.; et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J. Clin. Invest 2005, 115, 2223–2233. [Google Scholar]
  83. Marshak-Rothstein, A. Toll-Like receptors in systemic autoimmune disease. Nat. Rev. Immunol 2006, 6, 823–835. [Google Scholar]
  84. Jiang, D.; Liang, J.; Fan, J.; Yu, S.; Chen, S.; Luo, Y.; Prestwich, G.D.; Mascarenhas, M.M.; Garg, H.G.; Quinn, D.A.; et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med 2005, 11, 1173–1179. [Google Scholar]
  85. Pasare, C.; Medzhitov, R. Toll-Like receptors and acquired immunity. Semin. Immunol 2004, 16, 23–26. [Google Scholar]
  86. Giglia-Mari, G.; Zotter, A.; Vermeulen, W. DNA damage response. Cold Spring Harb. Perspect. Biol. 2011. [Google Scholar] [CrossRef]
  87. Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature 2009, 461, 1071–1078. [Google Scholar]
  88. Freund, A.; Orjalo, A.V.; Desprez, P.Y.; Campisi, J. Inflammatory networks during cellular senescence: Causes and consequences. Trends Mol. Med 2010, 16, 238–246. [Google Scholar]
  89. Tsuji, T.; Aoshiba, K.; Nagai, A. Alveolar cell senescence exacerbates pulmonary inflammation in patients with chronic obstructive pulmonary disease. Respiration 2010, 80, 59–70. [Google Scholar]
  90. Tsuji, T.; Aoshiba, K.; Nagai, A. Alveolar cell senescence in patients with pulmonary emphysema. Am. J. Respir. Crit. Care Med 2006, 174, 886–893. [Google Scholar]
  91. Mercado, N.; Thimmulappa, R.; Thomas, C.M.; Fenwick, P.S.; Chana, K.K.; Donnelly, L.E.; Biswal, S.; Ito, K.; Barnes, P.J. Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem. Biophys. Res. Commun 2011, 406, 292–298. [Google Scholar]
  92. Adcock, I.M.; Tsaprouni, L.; Bhavsar, P.; Ito, K. Epigenetic regulation of airway inflammation. Curr. Opin. Immunol 2007, 19, 694–700. [Google Scholar]
  93. Rahman, I.; Adcock, I.M. Oxidative stress and redox regulation of lung inflammation in COPD. Eur. Respir. J 2006, 28, 219–242. [Google Scholar]

Share and Cite

MDPI and ACS Style

Neofytou, E.; Tzortzaki, E.G.; Chatziantoniou, A.; Siafakas, N.M. DNA Damage Due to Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD). Int. J. Mol. Sci. 2012, 13, 16853-16864. https://doi.org/10.3390/ijms131216853

AMA Style

Neofytou E, Tzortzaki EG, Chatziantoniou A, Siafakas NM. DNA Damage Due to Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD). International Journal of Molecular Sciences. 2012; 13(12):16853-16864. https://doi.org/10.3390/ijms131216853

Chicago/Turabian Style

Neofytou, Eirini, Eleni G. Tzortzaki, Argiro Chatziantoniou, and Nikolaos M. Siafakas. 2012. "DNA Damage Due to Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD)" International Journal of Molecular Sciences 13, no. 12: 16853-16864. https://doi.org/10.3390/ijms131216853

Article Metrics

Back to TopTop