Epidermal growth factor strongly affects epithelial Na+ transport and barrier function in fetal alveolar cells, with minor sex-specific effects

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.

Social status and susceptibility to wildfire smoke among outdoor-housed female rhesus monkeys: A natural experiment

“…Other studies have reported sex-specific pollution effects on lung function and cytokines in primates and humans [ 68 , 69 , 70 , 71 ], and rank operates very differently in male primates (i.e., males physically fight to establish and re-establish rank, and mid-ranked males, often in conflict with animals both above and below them, display particularly high social vigilance [ 72 ] and plasma vasopressin [ 73 ]. Likewise, lung development, function, and volume vary by sex in human [ 74 , 75 , 76 ] and animal populations; one human study found that maternal and early-life stress reduced postnatal lung function among boys but not girls [ 71 ]. In mice, males have been shown more sensitive to in-utero second-hand smoke exposure than females during lung development [ 77 ].…”

Albumin Stimulates Epithelial Na+ Transport and Barrier Integrity by Activating the PI3K/AKT/SGK1 Pathway

“…Reverse transcription was carried out employing the Maxima H Minus DNA Synthesis Kit (Thermo Fisher Scientific). Real-time quantitative PCR (RT-qPCR) was performed in the CFX 96 Real-Time system (Bio-Rad, Munich, Germany) using the SYBR Select Master Mix (Fisher Scientific GmbH) and gene-specific primers [ 41 , 42 ] as described before [ 42 ]. The resulting molecule concentrations were normalized to a reference gene encoding for the mitochondrial ribosomal protein S18a (Mrps18a).…”

Y It Matters—Sex Differences in Fetal Lung Development

“…As discussed above, sex differences in EGF and GC signaling have been noted. Analyzing their effect on Na + transport demonstrated that chronic EGF treatment reduced ENaC mRNA levels and activity in both male and female FDLE cells [179]. In contrast, acute effects of EGF were sex-specific with a reduced Na + transport observed only in male FDLE cells [179].…”