Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition
Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition
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DOI：
10.1152/ajplung.00163.2014
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发表时间：
2015-01-01
影响因子：
4.9
通讯作者：
Tarran, Robert
中科院分区：
文献类型：
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作者：
Astrand, Annika B. M.;Hemmerling, Martin;Tarran, Robert
气道脱水会导致囊性纤维化和慢性支气管炎 (CB) 中的粘液淤积和细菌过度生长。高渗盐水补液是有效的，但作用持续时间短。我们测试了上皮钠通道 (ENaC) 抑制是否会在相当长的时间内补充正常和脱水气道的水分，从而增加粘液纤毛清除率 (MCC)。为此，我们使用了一种工具化合物（化合物 A），它在气道表面液体 (ASL) 中表现出纳摩尔 ENaC 亲和力和保留作用。使用在气液界面生长的正常人支气管上皮培养物 (HBEC)，我们使用短路电流 (I-sc) 和 ASL 高度测量来评估体外效力和功效，其中它分别抑制 I-sc 和增加 ASL 高度约 50%（6 小时时为 0.052 μM）。在改良的豚鼠气管电位差模型中研究了体内功效，其中我们观察到了 5 μg/kg (i.t.) 的有效剂量 (ED50)，并通过大鼠和绵羊的 MCC 测量，我们证明了分别在 100 μg/kg (i.t.) 和 75 μg/kg (i.t.) 时的最大清除率。 HBEC 中急性香烟烟雾引起的 ASL 高度降低被用来模拟 CB 患者的情况，预处理可防止香烟烟雾引起的 ASL 脱水并减轻纤毛跳动频率的降低。此外，当在暴露于香烟烟雾后添加时，化合物 A 增加了 ASL 补液率。总之，化合物 A 表现出显着的效果，并且在增加气道水合作用、纤毛功能和 MCC 之间存在联系。这些数据支持这样的假设：ENaC 抑制可能对恢复 CB 患者的粘液水合和运输有效。
Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis and chronic bronchitis (CB). Rehydration by hypertonic saline is efficacious but suffers from a short duration of action. We tested whether epithelial sodium channel (ENaC) inhibition would rehydrate normal and dehydrated airways to increase mucociliary clearance (MCC) over a significant time frame. For this, we used a tool compound (Compound A), which displays nanomolar ENaC affinity and retention in the airway surface liquid (ASL). Using normal human bronchial epithelial cultures (HBECs) grown at an air-liquid interface, we evaluated in vitro potency and efficacy using short-circuit current (I-sc) and ASL height measurements where it inhibited I-sc and increased ASL height by similar to 50% (0.052 mu M at 6 h), respectively. The in vivo efficacy was investigated in a modified guinea pig tracheal potential difference model, where we observed an effective dose (ED50) of 5 mu g/kg (i.t.), and by MCC measures in rats and sheep, where we demonstrated max clearance rates at 100 mu g/kg (i.t.) and 75 mu g/kg (i.t.), respectively. Acute cigarette smoke-induced ASL height depletion in HBECs was used to mimic the situation in patients with CB, and pretreatment prevented both cigarette smoke-induced ASL dehydration and lessened the decrease in ciliary beat frequency. Furthermore, when added after cigarette smoke exposure, Compound A increased the rate of ASL rehydration. In conclusion, Compound A demonstrated significant effects and a link between increased airway hydration, ciliary function, and MCC. These data support the hypothesis that ENaC inhibition may be efficacious in the restoration of mucus hydration and transport in patients with CB.