Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells

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.

The association between sex and neonatal respiratory distress syndrome

“…In retrospective analytic research of a sizable sample of italian neonatal hospitalization data, Condò et al [ 8 ] revealed that birth weight and sex also presented a risk effect on NRDS. The male disadvantage in NRDS was reported by Laube et al [ 9 ] in research of antenatal glucocorticoids stimulation of alveolar cell epithelial Na + transport. However, antenatal glucocorticoids administration had no sex-specific effects on Na + transport, indicating that antenatal glucocorticoids administration had no effect on the male disadvantage in NRDS.…”

Y It Matters—Sex Differences in Fetal Lung Development

“…Nevertheless, the study suggested that EGF unlikely represents the cause for the sex differences in Na + transport. Furthermore, GCs increased ENaC activity and mRNA expression in FDLE cells, independent of sex and inhibition of GR did not equalize Na + transport between male and female cells, suggesting that GR activity does not contribute to the increased Na + transport in females [106].…”

“…Their lungs at birth were severely atelectatic and development was impaired at the early canalicular stage [105]. In FDLE cells of fetal rats, GR mRNA expression was significantly higher in female cells, possibly rendering them more receptive to GCs [106]. In contrast, the total number of lung GR and the measured binding affinity did not significantly differ between male and female sheep fetuses [107].…”

The association between sex and neonatal respiratory distress syndrome

“…In retrospective analytic research of a sizable sample of Italian neonatal hospitalization data, Condò et al [8] revealed that birth weight and sex also presented a risk effect on NRDS. The male disadvantage in NRDS was reported by Laube et al [9] in research of antenatal glucocorticoids stimulation of alveolar cell epithelial Na + transport. However, antenatal glucocorticoids administration had no sex-speci c effects on Na + transport, indicating that antenatal glucocorticoids administration had no effect on the male disadvantage in NRDS.…”