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. 2025 Apr 28;26(1):165.
doi: 10.1186/s12931-025-03251-4.

Low levels of DNA repair enzyme NEIL2 May exacerbate inflammation and genomic damage in subjects with stable COPD and during severe exacerbations

Victor J Cardenas Jr  1   2   3 , Justin B Seashore  4 , Nisha Tapryal  5 , Moe Ameri  6 , Rosalinda Rivera  7 , Kabir Sharma  5 , Tapas Hazra  5   7   8
Affiliations

Low levels of DNA repair enzyme NEIL2 May exacerbate inflammation and genomic damage in subjects with stable COPD and during severe exacerbations

Victor J Cardenas Jr et al. Respir Res. .

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease that is an independent risk factor for lung cancer. Reduction in NEIL2 function, a DNA glycosylase involved in DNA repair during transcription, has 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 COPD. We investigated whether NEIL2 levels and oxidative DNA damage to the transcribed genome are reduced in individuals with stable COPD and during severe acute exacerbations of COPD (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 individuals without lung disease (controls). 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 fold change in NEIL2 mRNA levels were lower in individuals with stable COPD and AECOPD than in controls (0.72 for COPD, p = 0.029; 0.407 for AECOPD, p < 0.001). 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 < 0.001) and AECOPD (15.81, p < 0.001) groups than in the control group. The difference in fold change was also greater in the AECOPD group versus stable COPD p < 0.024). Cytokine 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 = 0.003).

Conclusions: NEIL2 mRNA levels are significantly reduced in individuals with COPD and may exacerbate DNA damage and inflammation. These results suggest a possible mechanism that increases inflammation and oxidative genomic damage in COPD.

Clinical trial number: Not applicable.

Keywords: Airway inflammation; COPD; Cancer; DNA repair; Eosinophils; Genomic damage; NEIL2.

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Conflict of interest statement

Declarations. Ethical approval: This single-center study was approved by the UTMB Institutional Review Board (#14–0131) for oral consent and performed in accordance with the Declaration of Helsinki in 1975 and as revised in 1983. All patient data were deidentified prior to performing the assays. No individual patient data or identifiers are included in the manuscript. All authors of the manuscript have read and agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
DNA glycosylase levels by group. Whisker plots displaying the expression levels of DNA glycosylase transcripts in the blood cells of stable COPD (n = 18) and AECOPD (n = 11) subjects vs. controls (n = 23). Boxes represent the interquartile range extending from the first to third quartiles, with the horizontal line representing the median value. Whiskers or error bars represent the maximum and minimum values, respectively; x in the box shows the mean. P values (unpaired two-tailed Student’s t test) vs. the control or stable COPD group are indicated
Fig. 2
Fig. 2
DNA damage by groups. Whisker plot displaying the levels of DNA lesions per Kb of genomic DNA in blood cells of stable COPD subjects and AECOPD subjects vs. the control group. Boxes represent the interquartile range extending from the first to third quartiles, with the horizontal line representing the median value. Whiskers or error bars represent the maximum and minimum values, respectively; x in the box shows the mean. B. Histogram showing the fold change in DNA lesions in the blood cells of control (n = 23), stable COPD (n = 18) and AECOPD (n = 11) subjects, as analyzed by LA‒qPCR. P values (unpaired two-tailed Student’s t test) vs. the control or stable COPD group are indicated
Fig. 3
Fig. 3
Correlation between NEIL2 mRNA levels and blood eosinophils in stable COPD subjects. The scatterplot displays the NEIL2 mRNA fold change versus the absolute eosinophil count in subjects with stable COPD. The line denotes Pearson product correlation with r = 0.737, p = 0.0027
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