Acute Regulation of the Epithelial Sodium Channel in Airway Epithelia by Proteases and Trafficking
Acute Regulation of the Epithelial Sodium Channel in Airway Epithelia by Proteases and Trafficking
复制标题
DOI：
10.1165/rcmb.2009-0348oc
复制
发表时间：
2010-12-01
影响因子：
6.4
通讯作者：
Butterworth, Michael B.
中科院分区：
文献类型：
--
作者：
Myerburg, Michael M.;Harvey, Peter R.;Butterworth, Michael B.
有效清除吸入病原体是肺部主要的先天防御机制，需要维持适当的气道表面液体（ASL）体积，以促进纤毛跳动并优化粘膜纤毛清除。通过上皮钠通道 (ENaC) 的 Na+ 吸收受到严格调节，并与氯离子运动一起提供最佳渗透梯度，以吸收气道腔中过多的液体，同时防止 ASL 过度脱水，从而影响肺部粘液清除。为了从管腔表面吸收过量的液体，ENaC 激活的局部机制允许在 ASL 体积扩大时增加 Na+ 的吸收。为了帮助定义这些调节机制，我们研究了 ASL 体积扩张对原代人支气管上皮 (HBE) 细胞培养物中 ENaC 活性的影响。我们发现内源性 ASL 快速稀释后 ENaC 活性显着增加。 Na+吸收增加的大约35%归因于蛋白酶对ENaC的激活。当布雷菲德菌素 A、诺考达唑或肌球蛋白轻链激酶抑制剂破坏膜运输时，Na+ 电流增加的其余部分被阻止，这表明运输与气道中的 ENaC 调节有关。这些发现表明，气道中 Na+ 的吸收受到通道到管腔表面的协调运输以及响应 ASL 体积扩张的 ENaC 蛋白水解激活的强烈调节。
Effective clearance of inhaled pathogens is the primary innate defense mechanism in the lung, and requires the maintenance of a proper airway surface liquid (ASL) volume to facilitate ciliary beat and optimize mucociliary clearance. Na+ absorption via the epithelial sodium channel (ENaC) is tightly regulated and, together with chloride movement, provides the optimal osmotic gradients to absorb excessive fluid in the airway lumen while preventing excessive ASL dehydration, which would compromise mucus clearance from the lung. To absorb excessive fluid from the luminal surface, a local mechanism of ENaC activation allows for an increase in Na+ absorption at times when the ASL volume is expanded. To help define these regulatory mechanisms, we examined the effects of ASL volume expansion on ENaC activity in primary human bronchial epithelial (HBE) cell cultures. We found that ENaC activity increases dramatically after rapid dilution of endogenous ASL. Approximately 35% of the increase in Na+ absorption was attributable to activation of ENaC by proteases. The remainder of the increase in Na+ current was prevented when membrane trafficking was disrupted with brefeldin A, nocodazole, or myosin light chain kinase inhibitors, demonstrating that trafficking is involved with ENaC regulation in the airway. These findings demonstrate that Na+ absorption in the airway is acutely modulated by the coordinated trafficking of channels to the luminal surface and by the proteolytic activation of ENaC in response to ASL volume expansion.