Male Sex is Associated with a Reduced Alveolar Epithelial Sodium Transport.

Till Kaltofen,Ulrich H Thome,Mandy Laube,Melanie Haase,Eric Feraille

doi:10.1371/journal.pone.0136178

Abstract

Respiratory distress syndrome (RDS) is the most frequent pulmonary complication in preterm infants. RDS incidence differs between genders, which has been called the male disadvantage. Besides maturation of the surfactant system, Na+ transport driven alveolar fluid clearance is crucial for the prevention of RDS. Na+ transport is mediated by the epithelial Na+ channel (ENaC) and the Na,K-ATPase, therefore potential differences in their expression or activity possibly contribute to the gender imbalance observed in RDS. Fetal distal lung epithelial (FDLE) cells of rat fetuses were separated by sex and analyzed regarding expression and activity of the Na+ transporters. Ussing chamber experiments showed a higher baseline short-circuit current (ISC) and amiloride-sensitive ΔISC in FDLE cells of female origin. In addition, maximal amiloride-sensitive ΔISC and maximal ouabain-sensitive ΔISC of female cells were higher when measured in the presence of a permeabilized basolateral or apical membrane, respectively. The number of FDLE cells per fetus recoverable during cell isolation was also significantly higher in females. In addition, lung wet-to-dry weight ratio was lower in fetal and newborn female pups. Female derived FDLE cells had higher mRNA levels of the ENaC- and Na,K-ATPase subunits. Furthermore, estrogen (ER) and progesterone receptor (PR) mRNA levels were higher in female cells, which might render female cells more responsive, while concentrations of placenta-derived sex steroids do not differ between both genders during fetal life. Inhibition of ER-β abolished the sex differences in Na+ transport and female cells were more responsive to estradiol stimulation. In conclusion, a higher alveolar Na+ transport, possibly attributable to a higher expression of hormone receptors in female FDLE cells, provides an explanation for the well known sex-related difference in RDS occurrence and outcome.

Highlights

Respiratory distress syndrome (RDS), known as hyaline membrane disease, is the leading cause of morbidity and mortality in preterm infants [1]
Males had a higher lung W/D weight ratio of 6.4 ± 0.1 compared to females with 6.0 ± 0.1 (p
The clinical use of antenatal steroids and surfactant replacement therapy reduced the risk for pulmonary complications in preterm infants yet the gender imbalance for respiratory distress still exists as current studies repeatedly showed [14,15]

Summary

Introduction

Respiratory distress syndrome (RDS), known as hyaline membrane disease, is the leading cause of morbidity and mortality in preterm infants [1]. Alveolar fluid clearance (AFC) is driven by unidirectional Na+ transport across the alveolar epithelia [5] In this process Na+ enters the apical membrane of alveolar type II (ATII) cells through epithelial Na+ channels (ENaC) and is actively extruded basolaterally by the Na,K-ATPase [6] (Fig 1). Disturbances of alveolar epithelial Na+ transport result in pulmonary fluid accumulation, which compromises gas exchange and represents another causative factor contributing to RDS in preterm infants [9,10]. Since estrogen and progesterone plasma concentrations are similar in male and female fetuses [26,27], female sex steroid levels per se are not likely the cause for sex differences in fetal lung development. The aim of this study was to analyze putative sex-related differences in Na+ transport across fetal alveolar epithelia and elucidate mechanisms regulating potential sex differences in alveolar Na+ transport

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