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

Abstract

AbstractBackgroundRespiratory tract colonisation withUreaplasmaspecies has been associated with the development of acute and long-term pulmonary morbidity in preterm infants. Apart from inflammation, the underlying mechanisms ofUreaplasma-driven lung disease are mainly unknown. The present investigation is the first to examine the influence of acuteUreaplasmainfection on critical mechanisms of alveolar fluid clearance in the immature lung.MethodsPrimary rat fetal distal lung epithelial (FDLE) cells were incubated with viableUreaplasmain 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 ofUreaplasmainfection resulting from significant inhibition of ENaC and Na,K-ATPase activities. Notably,Ureaplasmainduced phosphorylation of Erk1/2 – a well-known inhibitor of ENaC activity. Moreover,Ureaplasma-driven NH3production - and not the accompanying pH shift - inhibited the epithelial Na+transport. Co-incubation with flurofamide entirely restored Na+transport inUreaplasma-infected FDLE cells.ConclusionOur data demonstrate thatUreaplasmainfection significantly impairs epithelial Na+transport and subsequent fluid clearance in fetal alveolar cells – most likely by Erk1/2 phosphorylation. We identified NH3as the mediating virulence factor and were able to restore Na+transport by inhibiting theUreaplasma-specific urease. This is the first study to show a functional impairment of pulmonary epithelial cells uponUreaplasmainfection, revealing a potential mechanism ofUreaplasma-driven preterm lung disease.Take HomeWe reportUreaplasma-induced inhibition of epithelial Na+transport as a potential mechanism ofUreaplasma-driven preterm lung disease. NH3is identified as a virulence factor offering a potential therapeutic role for urease inhibitors in colonised infants.