Abstract
Male sex remains an independent risk factor for respiratory distress syndrome (RDS) in preterm infants. Insufficient Na+ transport-mediated alveolar fluid clearance contributes to RDS development and we previously demonstrated sex-specific differences in Na+ transport. The epidermal growth factor (EGF) is important during fetal lung development with possible influence on Na+ transport. Sex-specific effects of EGF during surfactant synthesis were shown. We thus determined whether EGF exerts sex-specific effects on Na+ transport in fetal alveolar cells. We analyzed sex-specific fetal distal lung epithelial (FDLE) cells exposed to EGF and related ligands with Ussing chambers, RT-qPCR and Western blots. EGF strongly reduced the epithelial Na+ channel (ENaC) mRNA levels in both male and female FDLE cells. This was corroborated by a markedly reduced ENaC activity, while amiloride-insensitive pathways as well as barrier function were raised by EGF. In contrast to chronic effects, acute effects of EGF were sex-specific, because Na+ transport was reduced only in males. AKT phosphorylation was elevated only in female cells, while pERK1/2 was increased in both male and female cells. EGF showed certain sex- and time-dependent effects in FDLE cells. Nevertheless, the results suggest that EGF is an unlikely cause for the sex-specific differences in Na+ transport.
Highlights
During fetal development, lung epithelial cells actively secrete fluid, thereby filling the developing lung
Three other members of this family have been identified: ErbB2, ErbB3, and ErbB4, which are capable of forming homodimers, heterodimers, and possibly higher-order oligomers. Despite their large degree of structural homology, ErbB family members differ from each other in their patterns of expression, ligand specificity, and intracellular substrates. Complementing these receptors is a family of ligands: e.g. epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) bind only to ErbB1 (EGFR), heparin-binding EGF (HB-EGF) binds to both ErbB1 and ErbB4, and neuregulin 1 (NRG1) which binds to ErbB3 and ErbB4
We addressed the effect of EGF on epithelial Na+ channels in male and female fetal distal lung epithelial (FDLE) cells separately
Summary
Lung epithelial cells actively secrete fluid, thereby filling the developing lung. Possibly contributing to the observed female a dvantage[15], while androgens and glucocorticoids were either lacking any effect or stimulated N a+ transport in both s exes[15,16] Another important growth factor during fetal lung development is the epidermal growth factor (EGF). Three other members of this family have been identified: ErbB2, ErbB3, and ErbB4, which are capable of forming homodimers, heterodimers, and possibly higher-order oligomers Despite their large degree of structural homology, ErbB family members differ from each other in their patterns of expression, ligand specificity, and intracellular substrates. We aimed to determine the impact of EGF and its related ligands on Na+ transport in sex-specific FDLE cells and reveal contributing pathways in this context
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