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[Preprint]. 2024 Sep 3:rs.3.rs-4849668.
doi: 10.21203/rs.3.rs-4849668/v1.

Suppression of the DNA repair enzyme NEIL2 promotes persistent inflammation and genomic damage in subjects with stable COPD and during severe exacerbations

Victor J Cardenas  1 , Justin B Seashore  2 , Nisha Tapryal  1 , Moe Ameri  1 , Rosalinda Rivera  1 , Kabir Sharma  1 , Tapas Hazra  1
Affiliations

Suppression of the DNA repair enzyme NEIL2 promotes persistent inflammation and genomic damage in subjects with stable COPD and during severe exacerbations

Victor J Cardenas et al. Res Sq. .

Update in

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease that is an independent risk factor for lung cancer. NEIL2, a DNA glycolase involved in DNA repair during transcription, has also been associated with an increased incidence of malignancies in humans. NEIL2 knockout mouse models have demonstrated increased inflammation and oxidative DNA damage in the lungs after exposure to an inflammatory insult, but data are lacking regarding NEIL2 function in individuals with stable COPD and during severe acute exacerbations of COPD (AECOPD). We investigated whether NEIL2 levels and oxidative DNA damage to the transcribed genome are altered in individuals with stable COPD and AECOPD.

Methods: The study was conducted at a single center in the US. Eligible subjects underwent a one-time 30 cc venous blood draw. The population consisted of 50 adults: 16 with stable COPD, 11 hospitalized for AECOPD, and 23 volunteers. We analyzed blood leukocytes for NEIL2 mRNA and DNA damage by RT-qPCR and LA-qPCR, respectively, in all groups. Plasma levels of seven biomarkers, CXCL1, CXCL8, CXCL9, CXCL10, CCL2, CCL11 and IL-6, were analyzed in the COPD groups using a magnetic bead panel (Millipore®).

Results: The NEIL2 mRNA levels were lower in individuals with stable COPD and AECOPD than in controls (0.72 for COPD, p = 0.0289; 0.407 for AECOPD, p = 0.0002). The difference in NEIL2 mRNA expression between the stable COPD group and AECOPD group was also statistically significant (p < 0.001). The fold change in DNA lesions per 10 kb of DNA was greater in the stable COPD (9.38, p < 0.0008) and AECOPD (15.81, p < 0.0004) groups than in the control group. The difference in fold change was also greater in the AECOPD group versus stable COPD p < 0.0236). Biomarker levels were not significantly different between the COPD groups. NEIL2 levels were correlated with plasma eosinophil levels in the stable COPD group (r = 0.737, p < 0.0027).

Conclusions: NEIL2 mRNA levels are significantly reduced in COPD subjects and are associated with increased DNA damage and inflammation. These results reveal a mechanism that promotes persistent airway inflammation and oxidative genomic damage and increases the risk of malignancy in this population.

Keywords: COPD; DNA repair; NEIL2; airway inflammation; cancer; eosinophils; genomic damage.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
DNA glycolase levels by group
Figure 2
Figure 2
DNA damage by groups
Figure 3
Figure 3
Correlation between Neil2 mRNA levels and blood eosinophils in stable COPD subjects
See this image and copyright information in PMC

References

    1. COPD Trends Brief: Mortality. American Lung Association; 2023. www.lung.org/research/trends-in-lung-disease/copd-trends-brief/copd-mort...
    1. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847–52. [Erratum, Thorax 2008;63:753.] - PMC - PubMed
    1. American Cancer Society, Key Statistics for Lung Cancer, 2023. www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html
    1. Husebø G. R., Nielsen R., Hardie J., Bakke P. S., Lerner L., D’Alessandro-Gabazza C., Gyuris J., Gabazza E., Aukrust P., & Eagan T. (2019). Risk factors for lung cancer in COPD - results from the Bergen COPD cohort study. Respiratory medicine, 152, 81–88. 10.1016/jjmed.2019.04.019 - DOI - PubMed
    1. Gagnat A. A., Gjerdevik M., Lie S. A., Gulsvik A., Bakke P., & Nielsen R. (2020). Acute exacerbations of COPD and risk of lung cancer in COPD patients with and without a history of asthma. European clinical respiratory journal, 7(1), 1799540. 10.1080/20018525.2020.1799540 - DOI - PMC - PubMed

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