Abstract
Preterm infants frequently suffer from respiratory distress syndrome (RDS), possibly due to lower expression of epithelial Na+ channels (ENaC). RDS incidence is sex-specific, affecting males almost twice as often. Despite the use of antenatal glucocorticoids (GCs), the sex difference persists. It is still controversial whether both sexes benefit equally from GCs. We previously showed that Na+ transport is higher in female compared with male fetal distal lung epithelial (FDLE) cells. Since GCs increase Na+ transport, we hypothesized that their stimulating effect might be sex-specific. We analyzed FDLE cells with Ussing chambers and RT-qPCR in the presence or absence of fetal serum. In serum-free medium, GCs increased the ENaC activity and mRNA expression, independent of sex. In contrast, GCs did not increase the Na+ transport in serum-supplemented media and abolished the otherwise observed sex difference. Inhibition of the GC receptor in the presence of serum did not equalize Na+ transport between male and female cells. The GC-induced surfactant protein mRNA expression was concentration and sex-specific. In conclusion, female and male FDLE cells exhibit no sex difference in response to GCs with regard to Na+ transport, and GR activity does not contribute to the higher Na+ transport in females.
Highlights
Pulmonary adaptation to air breathing is an indispensable step to extra-uterine survival
Assuming a potential sex difference in GC responsiveness, we first determined whether the glucocorticoid receptors (GR) mRNA level was differentially expressed between male and female fetal distal lung epithelial (FDLE) cells cultured in serum-supplemented medium (SS-Med)
GR mRNA expression was significantly higher in female FDLE cells (p < 0.05; Figure 1A), possibly rendering them more receptive to GCs
Summary
Pulmonary adaptation to air breathing is an indispensable step to extra-uterine survival. Male sex was associated with decreased Na+ transport and lower ENaC and Na,K-ATPase expression in fetal distal lung epithelial (FDLE) cells [8]. ENaC consists of three homologous subunits, α-, β- and γ-ENaC [9], and the Na,K-ATPase is composed of α1- and β1-subunits in alveolar type II (ATII) cells [10], which all exhibited lower mRNA expression in males. This was accompanied by higher lung fluid levels in male fetuses compared with females, suggesting lower or delayed onset AFC in males. Testosterone lacked any effect on Na+ transport in male and female FDLE cells, and flutamide, an androgen receptor antagonist, did not affect the gender imbalance, suggesting that Na+ transport is largely unaffected by androgens [11]
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