Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
Eur J Pharmacol. 2012 Dec 5;696(1-3):136-42. doi: 10.1016/j.ejphar.2012.08.015. Epub 2012 Sep 12.
Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV(1)) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV(1) level and inflammatory markers in COPD patients.We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV(1) decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting β2-agonists. Additionally we investigate the association of MRP1 variants with FEV(1) decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV(1) decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV(1) decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV(1) decline than in those with a weak staining. None of the variants was associated with FEV(1) decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV(1) decline occurring selectively in COPD patients with long-term (30-month) ICS therapy.
多药耐药相关蛋白 1（MRP1）降低了吸烟引起的氧化应激，而吸烟是慢性阻塞性肺疾病（COPD）的一个风险因素。我们之前的研究表明，MRP1 变体与一般人群中每年第一秒用力呼气量（FEV1）的水平和下降有关。此外，我们还表明，MRP1 变体与 COPD 患者的 FEV1 水平和炎症标志物也有关。我们在当前的研究中，使用安慰剂或吸入皮质类固醇（ICS）联合或不联合长效β2-激动剂，研究了支气管活检中 MRP1 蛋白表达与 COPD 患者 FEV1 下降之间的关系。此外，我们还研究了 MRP1 变体与 FEV1 下降之间的关系。在 110 例 COPD 患者中，对 MRP1 变体（rs212093、rs4148382、rs504348、rs4781699、rs35621）进行了基因分型。使用线性混合效应模型分析了 MRP1 变体和支气管活检中 MRP1 蛋白表达（在基线、6 个月和 30 个月时获得）与 FEV1 下降之间的相关性。在 30 个月的 ICS 治疗期间，MRP1 中度染色的患者的 FEV1 下降程度低于 MRP1 弱阳性染色的患者。在 6 个月后停用 ICS 并随后接受 24 个月安慰剂治疗的患者中，MRP1 中度染色与 FEV1 下降速度快于 MRP1 弱阳性染色的患者。没有一个变体与 FEV1 下降有关。我们的独特研究表明，支气管活检中 MRP1 蛋白表达在 COPD 患者长期（30 个月）ICS 治疗中选择性出现的 FEV1 下降中起作用。
