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bioRxiv · 10.1101/2024.02.14.580256

Inhibition of epithelial Na+ transport: novel mechanism of Ureaplasma-driven lung disease

Glaser, K.·Rieger, C.-B.·Paluszkiewicz, E.·Thome, U. H.·Laube, M.
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Abstract

BackgroundRespiratory tract colonisation with Ureaplasma species has been associated with the development of acute and long-term pulmonary morbidity in preterm infants. Apart from inflammation, the underlying mechanisms of Ureaplasma-driven lung disease are mainly unknown. The present investigation is the first to examine the influence of acute Ureaplasma infection on critical mechanisms of alveolar fluid clearance in the immature lung. MethodsPrimary rat fetal distal lung epithelial (FDLE) cells were incubated with viable Ureaplasma in the absence or presence of the urease inhibitor flurofamide. Na+ transport and activity of the epithelial Na+ channel (ENaC) and the Na,K-ATPase were determined in Ussing chambers. Barrier integrity, metabolic activity, gene expression, and kinase signalling were also assessed. ResultsWe found a 30-90% decrease of epithelial Na+ transport upon 24 hours of Ureaplasma infection resulting from significant inhibition of ENaC and Na,K-ATPase activities. Notably, Ureaplasma induced phosphorylation of Erk1/2 - a well-known inhibitor of ENaC activity. Moreover, Ureaplasma-driven NH3 production - and not the accompanying pH shift - inhibited the epithelial Na+ transport. Co-incubation with flurofamide entirely restored Na+ transport in Ureaplasma-infected FDLE cells. ConclusionOur data demonstrate that Ureaplasma infection significantly impairs epithelial Na+ transport and subsequent fluid clearance in fetal alveolar cells - most likely by Erk1/2 phosphorylation. We identified NH3 as the mediating virulence factor and were able to restore Na+ transport by inhibiting the Ureaplasma-specific urease. This is the first study to show a functional impairment of pulmonary epithelial cells upon Ureaplasma infection, revealing a potential mechanism of Ureaplasma-driven preterm lung disease. Take HomeWe report Ureaplasma-induced inhibition of epithelial Na+ transport as a potential mechanism of Ureaplasma-driven preterm lung disease. NH3 is identified as a virulence factor offering a potential therapeutic role for urease inhibitors in colonised infants.

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Glaser, K., Rieger, C.-B., Paluszkiewicz, E., Thome, U. H., Laube, M.. 2024-02-14. Inhibition of epithelial Na+ transport: novel mechanism of Ureaplasma-driven lung disease. https://doi.org/10.1101/2024.02.14.580256

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