H2O2 Stimulates Cystic Fibrosis Transmembrane Conductance Regulator through an Autocrine Prostaglandin Pathway, Using Multidrug-Resistant Protein-4
H2O2 Stimulates Cystic Fibrosis Transmembrane Conductance Regulator through an Autocrine Prostaglandin Pathway, Using Multidrug-Resistant Protein-4
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DOI：
10.1165/rcmb.2013-0156oc
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发表时间：
2013-10-01
影响因子：
6.4
通讯作者：
Salathe, Matthias
中科院分区：
文献类型：
--
作者：
Conner, Gregory E.;Ivonnet, Pedro;Salathe, Matthias
囊性纤维化跨膜传导调节因子（CFTR）活性对于维持气道表面液体深度以及因此维持粘膜纤毛清除率至关重要。在炎症性气道疾病期间增加的活性氧改变CFTR活性。在这里，H2 O2水平在正常人支气管上皮细胞培养分化的空气-液体界面的表面液体进行了估计，并H2 O2介导的CFTR活性的变化进行了检查。在Ussing室中，H2 O2诱导的阴离子电流对CFTR抑制剂CFTR（inh）172和GlyH-101敏感。这些电流在囊性纤维化患者的细胞中不存在。对大于500 mM H2 O2的反应是短暂的。环氧合酶抑制剂阻断H2 O2反应，EP 1和EP 4受体拮抗剂也是如此。多药耐药蛋白（MRP）抑制剂和针对MRP 4的短发夹RNA阻断H2 O2反应。EP 1和EP 4激动剂在对照和MRP 4敲低细胞中模拟H2 O2。因此，H2 O2激活前列腺素类通过EP 4和EP 1受体的合成、输出和结合，有趣的是，EP 1受体在正常的、分化的人气道上皮细胞中激活环磷酸腺苷途径，环磷酸腺苷途径又激活顶膜中的CFTR通道。
Cystic fibrosis transmembrane conductance regulator (CFTR) activity is essential for the maintenance of airway surface liquid depth, and therefore mucociliary clearance. Reactive oxygen species, increased during inflammatory airway diseases, alter CFTR activity. Here, H2O2 levels in the surface liquid of normal human bronchial epithelial cultures differentiated at the air-liquid interface were estimated, and H2O2-mediated changes in CFTR activity were examined. In Ussing chambers, H2O2-induced anion currents were sensitive to the CFTR inhibitors CFTR(inh)172 and GlyH-101. These currents were absent in cells from patients with cystic fibrosis. Responses to greater than 500 mM H2O2 were transient. Cyclooxygenase inhibitors blocked the H2O2 response, as did EP1 and EP4 receptor antagonists. Amultidrug-resistant protein (MRP) inhibitor and short hairpin RNA directed against MRP4 blocked H2O2 responses. EP1 and EP4 agonists mimicked H2O2 in both control and MRP4 knockdown cells. Thus, H2O2 activates the synthesis, export, and binding of prostanoids via EP4 and, interestingly, EP1 receptors in normal, differentiated human airway epithelial cells to activate cyclic adenosine monophosphate pathways that in turn activate CFTR channels in the apical membrane.