Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels.
Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels.
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DOI：
10.1186/1465-9921-15-69
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发表时间：
2014-06-23
影响因子：
5.8
通讯作者：
Cormet-Boyaka E
中科院分区：
文献类型：
--
作者：
Hassan F;Xu X;Nuovo G;Killilea DW;Tyrrell J;Da Tan C;Tarran R;Diaz P;Jee J;Knoell D;Boyaka PN;Cormet-Boyaka E
囊性纤维化跨膜传导调节因子（CFTR）是一种主要存在于气道上皮细胞中的氯离子通道。CFTR表达和/或功能降低导致气道表面液体（ASL）体积稳态受损，导致粘液积聚、细菌清除减少以及慢性感染和炎症。在对照组和GOLD 4期COPD患者的肺样本中评估CFTR表达和香烟烟雾金属含量。免疫组化和定量RT-PCR分别定量CFTR蛋白和mRNA。通过ICP-AES定量肺样品中存在的金属。使用原代人气道上皮细胞评估香烟烟雾对CFTR表达和功能下调的影响。通过将人支气管上皮细胞16 HBE 14 o-暴露于金属耗尽的香烟烟雾提取物，证实了在GOLD 4 COPD患者的肺样品中发现的涉及CFTR改变的铅金属的作用。我们发现，CFTR表达减少，在肺GOLD 4 COPD患者，特别是在支气管上皮细胞。对肺样本中存在的金属的评估显示，与对照吸烟者（GOLD 0）相比，GOLD 4 COPD患者中的镉和锰显著较高。暴露于香烟烟雾的原代人气道上皮细胞导致CFTR蛋白表达降低和气道表面液体高度降低。暴露于香烟烟雾的16 HBE 140细胞也表现出CFTR蛋白和mRNA水平的降低。在暴露前将金属去除和/或添加到香烟烟雾提取物中建立了它们在气道上皮细胞中CFTR降低中的作用。严重COPD患者肺中CFTR表达减少。这种效应与镉和锰的积累有关，表明这些金属在COPD发病机制中的作用。
The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that primarily resides in airway epithelial cells. Decreased CFTR expression and/or function lead to impaired airway surface liquid (ASL) volume homeostasis, resulting in accumulation of mucus, reduced clearance of bacteria, and chronic infection and inflammation. Expression of CFTR and the cigarette smoke metal content were assessed in lung samples of controls and COPD patients with established GOLD stage 4. CFTR protein and mRNA were quantified by immunohistochemistry and quantitative RT-PCR, respectively. Metals present in lung samples were quantified by ICP-AES. The effect of cigarette smoke on down-regulation of CFTR expression and function was assessed using primary human airway epithelial cells. The role of leading metal(s) found in lung samples of GOLD 4 COPD patients involved in the alteration of CFTR was confirmed by exposing human bronchial epithelial cells 16HBE14o- to metal-depleted cigarette smoke extracts. We found that CFTR expression is reduced in the lungs of GOLD 4 COPD patients, especially in bronchial epithelial cells. Assessment of metals present in lung samples revealed that cadmium and manganese were significantly higher in GOLD 4 COPD patients when compared to control smokers (GOLD 0). Primary human airway epithelial cells exposed to cigarette smoke resulted in decreased expression of CFTR protein and reduced airway surface liquid height. 16HBE14o-cells exposed to cigarette smoke also exhibited reduced levels of CFTR protein and mRNA. Removal and/or addition of metals to cigarette smoke extracts before exposure established their role in decrease of CFTR in airway epithelial cells. CFTR expression is reduced in the lungs of patients with severe COPD. This effect is associated with the accumulation of cadmium and manganese suggesting a role for these metals in the pathogenesis of COPD.
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DOI：
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