Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis
Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis
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DOI：
10.1152/ajplung.00437.2007
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发表时间：
2008-05-01
影响因子：
4.9
通讯作者：
Pilewski, Joseph M.
中科院分区：
文献类型：
--
作者：
Myerburg, Mike M.;McKenna, Erin E.;Pilewski, Joseph M.
气道表面液体（ASL）吸收是由Na+通过上皮Na+通道（ENaC）进入启动的，这建立了一个渗透梯度，将液体从腔气道表面驱动到浆膜气道表面。我们和其他人最近报道了蛋白酶/抗蛋白酶平衡调节人气道上皮细胞（HAEC）中的ENaC，并提供了ASL体积自动调节的机制。在囊性纤维化（CF）中，这种平衡被扰乱，导致ENaC的组成性蛋白水解活化和这种气道疾病的病理性Na+高吸收特征。前列腺素是一种糖基磷脂酰肌醇锚定的丝氨酸蛋白酶，其激活ENaC并在气道内衬的表面上皮上表达。在这份报告中，我们提出的证据表明，前列腺素的表达是由ASL体积调节，允许增加ENaC的蛋白水解激活时，ASL体积高。前列腺素活性进一步由同源丝氨酸蛋白酶抑制剂蛋白酶连接蛋白-1（PN-1）调节，其在HAEC中表达，并通过与前列腺素形成无活性复合物并阻止前列腺素的蛋白水解加工来抑制Na+吸收。尽管这些机制响应于非CF上皮中的ASL体积调节前列腺素表达，但从CF患者培养的HAEC在上皮表面上表达多50%的前列腺素。这些研究结果表明，涉及前列腺素（一种上游前列腺素活化蛋白酶）和PN-1的蛋白水解级联调节气道中的Na+吸收，并且异常的前列腺素表达有助于CF患者中ENaC的过度蛋白水解活化。
Airway surface liquid (ASL) absorption is initiated by Na+ entry via epithelial Na+ channels ( ENaC), which establishes an osmotic gradient that drives fluid from the luminal to serosal airway surface. We and others have recently reported that a protease/anti-protease balance regulates ENaC in human airway epithelial cells ( HAEC) and provides a mechanism for autoregulation of ASL volume. In cystic fibrosis (CF), this balance is disturbed, leading to constitutive proteolytic activation of ENaC and the pathological Na+ hyperabsorption characteristic of this airway disease. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that activates ENaC and is expressed on the surface epithelium lining the airway. In this report we present evidence that prostasin expression is regulated by the ASL volume, allowing for increased proteolytic activation of ENaC when the ASL volume is high. Prostasin activity is further regulated by the cognate serpin protease nexin-1 (PN-1), which is expressed in HAEC and inhibits Na+ absorption by forming an inactive complex with prostasin and preventing the proteolytic processing of prostasin. Whereas these mechanisms regulate prostasin expression in response to ASL volume in non-CF epithelia, HAEC cultured from CF patients express > 50% more prostasin on the epithelial surface. These findings suggest that a proteolytic cascade involving prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na+ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in CF patients.