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XB-ART-50331
Dev Biol December 15, 2015; 408 (2): 292-304.

ATP4a is required for development and function of the Xenopus mucociliary epidermis - a potential model to study proton pump inhibitor-associated pneumonia.

Walentek P , Beyer T , Hagenlocher C , Müller C , Feistel K , Schweickert A , Harland RM , Blum M .


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.

PubMed ID: 25848696
PMC ID: PMC4592800
Article link: Dev Biol
Grant support: [+]
Genes referenced: foxa1 foxi1 foxj1 tuba4a tph1 atp4a actl6a cat.2 dkk1 foxj1.2 gnl3 mcc mcidas myb nfs1 notch1 nsd1 ptch1 shh sult1a1
Antibodies: Atp4a
Morpholinos: atp4a MO1 atp4a MO2

Disease Ontology terms: pneumonia
OMIMs: HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT

Article Images: [+] show captions
References:
Altman, 2007, Pubmed [+]


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