Oxidative stress and Nrf2 expression in peripheral blood mononuclear cells derived from COPD patients: an observational longitudinal study

Background A persistent low inflammatory-oxidative status and the inadequacy of the antioxidant nuclear factor-E2-related factor 2 (Nrf2) have been implicated in chronic obstructive pulmonary disease (COPD) progression. Therefore this study was aimed to assess the association between lung function decline and oxidative-inflammatory markers and Nrf2 signaling pathway expression in peripheral blood mononuclear cells (PBMCs) over time. Methods 33 mild-moderate COPD outpatients (mean age 66.9 +/- 6.9 years) were age-sex matched with 37 no-COPD subjects. A clinical evaluation, blood sampling tests and a spirometry were performed at baseline and after a mean follow-up of 49.7 +/- 6.9 months. Results In COPD, compared to no-COPD, we found a faster lung function decline at follow-up. Although similar prevalence of smoking, hypertension, diabetes and dyslipidemia, systemic markers of inflammation (hs-CRP and white blood cells, WBCs) and oxidative stress (8-isoprostane) were significantly increased in COPD at follow-up, while the antioxidant glutathione (GSH) was significantly reduced. Moreover the expression of Nrf2 and of Nrf2-related genes heme oxygenase (HO)-1 and glutamate-cysteine ligase catalytic (GCLC) subunit in PBMCS were significantly down-regulated in COPD at follow-up, whereas no changes were observed in no-COPD. The percent variation (Delta) of FEV1 detected after the follow-up in COPD patients was directly correlated with Delta Nrf2 (r = 0.826 p < 0.001), Delta HO-1 (r = 0.820, p < 0.001) and Delta GCLC (r = 0.840, p < 0.001). Moreover Delta FEV1 was also directly correlated with Delta GSH (r = 0.595, p < 0.01) and inversely correlated with Delta 8-iso (r = - 0.587, p < 0.01) and with baseline smoking history (r = - 0.39, p < 0.03). No correlation was found between Delta FEV1, Delta CRP and Delta WBCs. By means of hierarchical stepwise multiple linear regression, taking into account other baseline key factors related to FEV1, Delta Nrf2, Delta HO-1and Delta GCLC were found to be significant predictors of Delta FEV1, explaining 89.5% of its variance. Conclusions Although our results must be confirmed in larger trial they suggest that the down-regulation of Nrf2/ARE gene expression in PBMCs may be one of the determinants of FEV1 decline and of COPD progression. Therefore the future possibility to counteract Nrf2 decline in COPD patients may help in reducing the negative effects of the oxidative stress-induced progression of the disease.