Neutrophil elastase induces MUC5AC messenger RNA expression by an oxidant-dependent mechanism
Neutrophil elastase induces MUC5AC messenger RNA expression by an oxidant-dependent mechanism
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DOI：
10.1378/chest.117.5_suppl_1.317s
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发表时间：
2000-05-01
期刊：
影响因子：
9.6
通讯作者：
Voynow, J
中科院分区：
文献类型：
--
作者：
Fischer, B;Voynow, J
囊性纤维化、慢性支气管炎和病毒或污染引发的哮喘等气道疾病有两个常见的病理特征：气道粘液阻塞和中性粒细胞为主的气道炎症。中性粒细胞将高浓度的弹性蛋白酶（中性粒细胞弹性蛋白酶[NE]）（一种丝氨酸蛋白酶）释放到气道中；暴露于弹性蛋白酶会导致分泌性化生和粘蛋白糖蛋白的产生/分泌增加。我们之前已经证明，NE 可以增加肺腺癌细胞系 A549 和培养的正常人支气管上皮细胞中呼吸道粘蛋白 MUC5AC 的基因表达。在本研究中，我们探讨了 NE 调节的 MUC5AC 基因表达所需的细胞内信号传导机制，在 NE 刺激之前和期间，用二甲基硫脲（DMTU；4 mM 和 40 mM）（羟自由基、过氧亚硝酸盐和其他羟基化产物的清除剂）处理 A549 细胞。 DMTU 抑制 NE 诱导的 MUC5AC 表达。此外，使用细胞内氧化还原指示剂二氯二氢荧光素，我们发现在 A549 细胞和培养的正常人支气管上皮细胞中，NE 处理都会诱导氧化应激。这些结果支持活性氧介导 NE 诱导的 MUC5AC 基因表达的作用。
Airway diseases such as cystic fibrosis, chronic bronchitis, and viral- or pollution-triggered asthma have two common pathologic features: mucus obstruction of the airways, and neutrophil-predominant airway inflammation. Neutrophils release high concentrations of elastase (neutrophil elastase [NE]), a serine protease, into the airways; exposure to elastase results in secretory metaplasia and increased production/secretion of mucin glycoproteins. We have previously shown that NE increases gene expression of a respiratory mucin, MUC5AC, in both A549, a lung adenocarcinoma cell line, and cultured normal human bronchial epithelial cells. In this study, we explored the intracellular signaling mechanisms required for NE-regulated MUC5AC gene expression, A549 cells were treated with dimethylthiourea (DMTU; 4 mM and 40 mM), a scavenger of hydroxyl radical, peroxynitrite, and other hydroxylated products, prior to and during NE stimulation. DMTU inhibited NE-induced MUC5AC expression. Furthermore, using dichlorodihydrofluorescein, an intracellular redox indicator, we showed that in both A549 cells and cultured normal human bronchial epithelial cells, NE treatment induced oxidative stress. These results support the role of reactive oxygen species mediating NE-induced MUC5AC gene expression.