ATP4a is required for development and function of the Xenopus mucociliary epidermis - a potential model to study proton pump inhibitor-associated pneumonia.
ATP4a is required for development and function of the Xenopus mucociliary epidermis - a potential model to study proton pump inhibitor-associated pneumonia.
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非洲爪蟾粘液纤毛表皮的发育和功能需要 ATP4a——这是研究质子泵抑制剂相关性肺炎的潜在模型
DOI：
10.1016/j.ydbio.2015.03.013
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发表时间：
2015
影响因子：
2.7
通讯作者：
Harland
中科院分区：
文献类型：
--
作者：
Walentek;Hagenlocher;Hagenlocher;Müller;Feistel;Schweickert;Harland
质子泵抑制剂 (PPI) 以胃 H+/K+ATP 酶 (ATP4) 为靶点，是最常用的处方药物之一。 PPI 用于治疗溃疡，并作为住院患者胃食管反流病的预防措施。 PPI 治疗与气道感染（即社区和医院获得性肺炎）风险增加相关。然而，这种相关性的原因仍然难以捉摸。非洲爪蟾胚表皮越来越多地被用作研究气道样粘液纤毛上皮的模型。在这里，我们使用这个模型来解决 ATP4 抑制如何影响人类气道上皮功能。我们证明 atp4 敲低会干扰纤毛驱动的细胞外液流动的产生。表皮中需要 ATP4a 和经典 Wnt 信号传导来表达 offoxj1（运动纤毛发生的转录调节因子）。 ATP4/Wnt 模块激活纤毛细胞命运规范下游的foxj1。在表皮多纤毛细胞 (MCC) 中，ATP4a 对于正常的 myb 表达、顶端肌动蛋白形成、基体对接和基体排列也是必需的。此外，表皮中 ATP4 依赖性 Wnt/β-catenin 信号传导是 forfoxa1 介导的小分泌细胞 (SSC) 规范的先决条件。 SSC 将血清素和其他物质释放到介质中，从而调节 MCC 中的纤毛跳动并保护上皮免受感染。成熟粘液纤毛上皮中 ATP4 的药理学抑制也会导致 MCC 损失，并导致粘液纤毛清除受损。这些数据强烈表明，人类患者中 PPI 相关性肺炎可能至少部分与气道粘液纤毛上皮功能障碍有关。
Proton pump inhibitors (PPIs), which target gastric H+/K+ATPase (ATP4), are among the most commonly prescribed drugs. PPIs are used to treat ulcers and as a preventative measure against gastroesophageal reflux disease in hospitalized patients. PPI treatment correlates with an increased risk for airway infections, i.e. community- and hospital-acquired pneumonia. The cause for this correlation, however, remains elusive. TheXenopusembryonic epidermis is increasingly being used as a model to study airway-like mucociliary epithelia. Here we use this model to address how ATP4 inhibition may affect epithelial function in human airways. We demonstrate thatatp4aknockdown interfered with the generation of cilia-driven extracellular fluid flow. ATP4a and canonical Wnt signaling were required in the epidermis for expression offoxj1, a transcriptional regulator of motile ciliogenesis. The ATP4/Wnt module activatedfoxj1downstream of ciliated cell fate specification. In multiciliated cells (MCCs) of the epidermis, ATP4a was also necessary for normalmybexpression, apical actin formation, basal body docking and alignment of basal bodies. Furthermore, ATP4-dependent Wnt/β-catenin signaling in the epidermis was a prerequisite forfoxa1-mediated specification of small secretory cells (SSCs). SSCs release serotonin and other substances into the medium, and thereby regulate ciliary beating in MCCs and protect the epithelium against infection. Pharmacological inhibition of ATP4 in the mature mucociliary epithelium also caused a loss of MCCs and led to impaired mucociliary clearance. These data strongly suggest that PPI-associated pneumonia in human patients might, at least in part, be linked to dysfunction of mucociliary epithelia of the airways.
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影响因子：
4
作者：
Ramsay EN;Pratt NL;Ryan P;Roughead EE
通讯作者：
Roughead EE
DOI：
10.1513/pats.201103-023sd
发表时间：
2011-09-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Zariwala, Maimoona A;Omran, Heymut;Ferkol, Thomas W
通讯作者：
Ferkol, Thomas W
影响因子：
11.8
作者：
Dehring, Deborah A. Klos;Vladar, Eszter K.;Werner, Michael E.;Mitchell, Jennifer W.;Hwang, Peter;Mitchell, Brian J.
通讯作者：
Mitchell, Brian J.
血清素通过小鼠气管中乙酰胆碱独立的途径增加纤毛驱动的颗粒运输
影响因子：
3.7
作者：
P. König;B. Krain;G. Krasteva;W. Kummer
通讯作者：
W. Kummer
人体组织中胃 H /K ATP 酶的系统表达谱
影响因子：
1.9
作者：
M. Herrmann;Jens Selige;S. Raffael;G. Sachs;A. Brambilla;T. Klein
通讯作者：
T. Klein