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 (Δ) of FEV1 detected after the follow-up in COPD patients was directly correlated with ΔNrf2 (r = 0.826 p < 0.001), ΔHO-1 (r = 0.820, p < 0.001) and ΔGCLC (r = 0.840, p < 0.001). Moreover ΔFEV1 was also directly correlated with ΔGSH (r = 0.595, p < 0.01) and inversely correlated with Δ8-iso (r = - 0.587, p < 0.01) and with baseline smoking history (r = - 0.39, p < 0.03). No correlation was found between ΔFEV1, ΔCRP and ΔWBCs. By means of hierarchical stepwise multiple linear regression, taking into account other baseline key factors related to FEV1, ΔNrf2, ΔHO-1and ΔGCLC were found to be significant predictors of ΔFEV1, 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.

中文翻译：

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慢性阻塞性肺病患者外周血单个核细胞中的氧化应激和Nrf2表达：一项纵向观察性研究。

背景技术持续的低炎症氧化状态和抗氧化剂核因子-E2相关因子2（Nrf2）不足与慢性阻塞性肺疾病（COPD）的发展有关。因此，本研究旨在评估随着时间的过去，外周血单个核细胞（PBMC）中肺功能下降与氧化性炎症标记物和Nrf2信号通路表达之间的关联。方法33例轻度中度COPD门诊患者（平均年龄66.9±6.9岁）与37名非COPD患者年龄性别匹配。在基线和平均随访时间为49.7±6.9个月后，进行了临床评估，血液采样测试和肺活量测定。结果在COPD中，与未COPD相比，我们发现随访时肺功能下降更快。尽管吸烟，高血压的患病率相似，糖尿病和血脂异常时，随访时COPD的炎症系统指标（hs-CRP和白细胞，WBC）和氧化应激（8-异前列腺素）显着增加，而抗氧化剂谷胱甘肽（GSH）显着降低。此外，随访时COPD中PBMCS中Nrf2和Nrf2相关基因血红素加氧酶（HO）-1和谷氨酸半胱氨酸连接酶催化性（GCLC）亚基的表达显着下调，而未观察到无改变。 COPD。COPD患者随访后检测到的FEV1的百分比变化（Δ）与ΔNrf2（r = 0.826 p <0.001），ΔHO-1（r = 0.820，p <0.001）和ΔGCLC（r = 0.840， p <0.001）。此外，ΔFEV1也与ΔGSH直接相关（r = 0.595，p <0.01），与Δ8-iso反相关（r =-0.587，p <0）。01）和基线吸烟史（r =-0.39，p <0.03）。在ΔFEV1，ΔCRP和ΔWBC之间没有发现相关性。通过分层逐步多元线性回归，考虑到与FEV1相关的其他基线关键因素，发现ΔNrf2，ΔHO-1和ΔGCLC是ΔFEV1的重要预测因子，解释了其方差的89.5％。结论尽管我们的结果必须在更大的试验中得到证实，但它们表明PBMC中Nrf2 / ARE基因表达的下调可能是FEV1下降和COPD进展的决定因素之一。因此，将来在COPD患者中抵消Nrf2下降的可能性可能有助于减少氧化应激诱导的疾病进展的负面影响。通过分层逐步多元线性回归，考虑到与FEV1相关的其他基线关键因素，发现ΔNrf2，ΔHO-1和ΔGCLC是ΔFEV1的重要预测因子，解释了其方差的89.5％。结论尽管我们的结果必须在更大的试验中得到证实，但它们表明PBMC中Nrf2 / ARE基因表达的下调可能是FEV1下降和COPD进展的决定因素之一。因此，将来在COPD患者中抵消Nrf2下降的可能性可能有助于减少氧化应激诱导的疾病进展的负面影响。通过分层逐步多元线性回归，考虑到与FEV1相关的其他基线关键因素，发现ΔNrf2，ΔHO-1和ΔGCLC是ΔFEV1的重要预测因子，解释了其方差的89.5％。结论尽管我们的结果必须在更大的试验中得到证实，但它们表明PBMC中Nrf2 / ARE基因表达的下调可能是FEV1下降和COPD进展的决定因素之一。因此，将来在COPD患者中抵消Nrf2下降的可能性可能有助于减少氧化应激诱导的疾病进展的负面影响。结论尽管我们的结果必须在更大的试验中得到证实，但它们表明PBMC中Nrf2 / ARE基因表达的下调可能是FEV1下降和COPD进展的决定因素之一。因此，将来在COPD患者中抵消Nrf2下降的可能性可能有助于减少氧化应激诱导的疾病进展的负面影响。结论尽管我们的结果必须在更大的试验中得到证实，但它们表明PBMC中Nrf2 / ARE基因表达的下调可能是FEV1下降和COPD进展的决定因素之一。因此，将来在COPD患者中抵消Nrf2下降的可能性可能有助于减少氧化应激诱导的疾病进展的负面影响。