Nrf2 expression is increased in peripheral blood mononuclear cells derived from mild-moderate ex-smoker COPD patients with persistent oxidative stress.
Nrf2 expression is increased in peripheral blood mononuclear cells derived from mild-moderate ex-smoker COPD patients with persistent oxidative stress.
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DOI：
10.2147/copd.s102218
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发表时间：
2016
影响因子：
2.8
通讯作者：
Cominacini L
中科院分区：
文献类型：
--
作者：
Fratta Pasini AM;Ferrari M;Stranieri C;Vallerio P;Mozzini C;Garbin U;Zambon G;Cominacini L
抗氧化核因子E2相关因子2（Nrf 2）和内质网应激介导的未折叠蛋白反应不足与严重慢性阻塞性肺疾病（COPD）和吸烟诱导的肺气肿有关。由于有证据表明上调Nrf 2表达的能力可能影响COPD的进展，并且到目前为止在患有轻度-中度COPD的戒烟者中没有数据，因此本研究首先旨在评估与吸烟习惯匹配的非COPD受试者相比，患有COPD的轻度-中度戒烟者的外周血单核细胞（PBMC）中的Nrf 2和未折叠蛋白应答表达。然后，我们测试了戒烟后氧化应激是否持续存在，以及相同受试者PBMC中氧化磷脂（磷脂1-棕榈酰-2-花生四烯酰-sn-甘油基-3-磷酸胆碱[oxPAPC]的氧化产物）的浓度是否可能在确定Nrf 2上调中起致病作用。COPD组Nrf 2及其相关基因血红素氧合酶-1的表达（mRNA和蛋白）均显著增加，而未折叠蛋白反应无差异。COPD患者血浆丙二醛（氧化应激的循环标志物）和PBMC中的oxPAPC显著高于非COPD受试者。COPD患者PBMC中NADPH氧化酶亚基p47 phox表达增加，且与oxPAPC表达直接相关，提示oxPAPC可能是氧化应激诱导Nrf 2表达上调的决定因素之一。最后，我们还表明，肺功能与血浆丙二醛和Nrf 2和血红素氧合酶-1 mRNA的表达在所有受试者呈负相关。我们的研究结果表明，轻度-中度COPD戒烟者可能能够通过增加Nrf 2/抗氧化反应元件的表达来抵消氧化应激。由于Nrf 2衰竭显著促进COPD的发展，我们的研究结果表明，预防Nrf 2减少的可能性可能会开辟一个新的场景，有助于预防氧化应激相关的肺功能下降。
Inadequacy of antioxidant nuclear factor-E2-related factor 2 (Nrf2) and endoplasmic reticulum stress-mediated unfolded protein response has been implicated in severe chronic obstructive pulmonary disease (COPD) and cigarette smoking-induced emphysema. As evidence suggests that the ability to upregulate Nrf2 expression may influence the progression of COPD and no data exist up to now in ex-smokers with mild–moderate COPD, this study was first aimed to evaluate Nrf2 and unfolded protein response expression in peripheral blood mononuclear cells (PBMC) of mild–moderate ex-smokers with COPD compared to smoking habit-matched non-COPD subjects. Then, we tested whether oxidative stress persists after cigarette smoking cessation and whether the concentrations of oxidized phospholipids (oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine [oxPAPC]) in the PBMC of the same subjects may have a causative role in determining the upregulation of Nrf2. The expression (mRNA and protein) of Nrf2 and of its related gene heme oxygenase-1 was significantly increased in COPD group without differences in the unfolded protein response. Plasma malondialdehyde, the circulating marker of oxidative stress, and oxPAPC in PBMC were significantly higher in COPD than in non-COPD subjects. The fact that the expression of p47phox, a subunit of NADPH oxidase, was increased in PBMC of COPD patients and that it was directly correlated with oxPAPC may indicate that oxPAPC may be one of the determinants of oxidative stress-induced Nrf2 upregulation. Finally, we also demonstrated that lung function inversely correlated with plasma malondialdehyde and with Nrf2 and heme oxygenase-1 mRNA expression in all subjects. Our results indicate that mild–moderate ex-smokers with COPD may be able to counteract oxidative stress by increasing the expression of Nrf2/antioxidant-response elements. Because Nrf2 failure significantly contributes to the development of COPD, our findings suggest that the possibility to prevent Nrf2 reduction may open a new scenario in helping to prevent the oxidative stress-associated lung function decline.