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

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.