Glucocorticoids Distinctively Modulate the CFTR Channel with Possible Implications in Lung Development and Transition into Extrauterine Life

Abstract

During fetal development, the lung is filled with fluid that is secreted by an active Cl- transport promoting lung growth. The basolateral Na+,K+,2Cl- cotransporter (NKCC1) participates in Cl- secretion. The apical Cl- channels responsible for secretion are unknown but studies suggest an involvement of the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is developmentally regulated with a high expression in early fetal development and a decline in late gestation. Perinatal lung transition is triggered by hormones that stimulate alveolar Na+ channels resulting in fluid absorption. Little is known on how hormones affect pulmonary Cl- channels. Since the rise of fetal cortisol levels correlates with the decrease in fetal CFTR expression, a causal relation may be assumed. The aim of this study was to analyze the influence of glucocorticoids on pulmonary Cl- channels. Alveolar cells from fetal and adult rats, A549 cells, bronchial Calu-3 and 16HBE14o- cells, and primary rat airway cells were studied with real-time quantitative PCR and Ussing chambers. In fetal and adult alveolar cells, glucocorticoids strongly reduced Cftr expression and channel activity, which was prevented by mifepristone. In bronchial and primary airway cells CFTR mRNA expression was also reduced, whereas channel activity was increased which was prevented by LY-294002 in Calu-3 cells. Therefore, glucocorticoids strongly reduce CFTR expression while their effect on CFTR activity depends on the physiological function of the cells. Another apical Cl- channel, anoctamin 1 showed a glucocorticoid-induced reduction of mRNA expression in alveolar cells and an increase in bronchial cells. Furthermore, voltage-gated chloride channel 5 and anoctamine 6 mRNA expression were increased in alveolar cells. NKCC1 expression was reduced by glucocorticoids in alveolar and bronchial cells alike. The results demonstrate that glucocorticoids differentially modulate pulmonary Cl- channels and are likely causing the decline of CFTR during late gestation in preparation for perinatal lung transition.

Role of Basal Hormones on Sweat Rate and Sweat Na+ Loss in Elite Women Soccer Players

“…We recently showed in male elite soccer players that basal cortisol (directly) and the testosterone/cortisol ratio (inversely) may influence sweat rate and Na + loss during a 90-min soccer practice [10]. This association was supported by in vitro and animal model studies in which cortisol [11] and testosterone [12] were shown to regulate the CFTR protein. With regards to sweat rate and sweat Na + loss during training or match-play in elite women soccer players, only two published studies exist showing interindividual variations [13,14].…”

Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone

“…To date, little is known about the effect of hormones on CFTR function, which appears to differ between the distal and the proximal airways. Our previous study showed that GCs reduced CFTR expression and activity in distal lung epithelial cells, which are responsible for gas exchange and fluid absorption [ 9 ]. In contrast, GCs stimulated CFTR activity in the air conducting proximal airways, which are responsible for MCC.…”

Postnatal decrease of cystic fibrosis transmembrane conductance regulator gene expression in nasal epithelium of healthy newborn infants

“…In addition, we found that the decrease in CFTR expression was more pronounced in the caesarean than vaginal group. This was somewhat unexpected, as glucocorticoids reduce CFTR expression in vitro and in rat lungs in a dose‐dependent manner . Also, stress hormones’ – cortisol and catecholamines – concentrations in human cord blood are markedly higher in vaginal than caesarean births .…”

“…The foetal lung is filled with fluid as a result of the active ion transport towards the alveolar lumen, thereby promoting early lung development . In late gestation and the perinatal period, the transition to extrauterine life requires a switch from fluid secretion to absorption.…”

“…During gestation, the foetal airway epithelial cystic fibrosis transmembrane conductance regulator (CFTR) mRNA gradually declines, enabling epithelial sodium channel activity and lung fluid absorption to increase . Data on CFTR gene expression and chloride transport in the airways remain scarce during early postnatal adaptation and are primarily based on in vitro and animal studies . Our aim was to examine changes in airway epithelial CFTR gene expression in nasal samples taken from human newborn infants during the critical transition to air breathing.…”