title: ATP4a is required for development and function of the Xenopus mucociliary epidermis - a potential model to study proton pump inhibitor-associated pneumonia.
abstract: 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. The Xenopus embryonic 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 that atp4a knockdown interfered with the generation of cilia-driven extracellular fluid flow. ATP4a and canonical Wnt signaling were required in the epidermis for expression of foxj1, a transcriptional regulator of motile ciliogenesis. The ATP4/Wnt module activated foxj1 downstream of ciliated cell fate specification. In multiciliated cells (MCCs) of the epidermis, ATP4a was also necessary for normal myb expression, apical actin formation, basal body docking and alignment of basal bodies. Furthermore, ATP4-dependent Wnt/β-catenin signaling in the epidermis was a prerequisite for foxa1-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.
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany; Department of Molecular and Cell Biology, Center for Integrative Genomics, University of California at Berkeley, Berkeley, CA 94720, USA. Electronic address: walentek@berkeley.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Walentek
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Beyer
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Hagenlocher
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Müller
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Feistel
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schweickert
authors.affiliation: Department of Molecular and Cell Biology, Center for Integrative Genomics, University of California at Berkeley, Berkeley, CA 94720, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Harland
authors.affiliation: Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Blum
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003428:Cross Infection / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009079:Mucociliary Clearance / Q000187:drug effects* / Q000502:physiology; D011014:Pneumonia / Q000209:etiology* / Q000503:physiopathology; D054328:Proton Pump Inhibitors / Q000009:adverse effects*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*
chemical_list: C490956:FOXJ1 protein, Xenopus; D051858:Forkhead Transcription Factors; D054328:Proton Pump Inhibitors; D029867:Xenopus Proteins; C579782:ATP4a protein, Xenopus; D017506:H(+)-K(+)-Exchanging ATPase
keywords: ATP4; Cilia; Proton pump inhibitor; Small secretory cells; Wnt; Xenopus laevis
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