Prenatal Estrogen and Progesterone Deprivation Impairs Alveolar Formation and Fluid Clearance in Newborn Piglets (original) (raw)
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Early Human Development, 2009
Background: Vascular endothelial growth factor (VEGF) is essential for embryonic lung development and has been shown to be regulated by estradiol (E2) and progesterone (P). Aim: To investigate the effects of prenatal E2 and P withdrawal by specific receptor antagonists on the mRNA expression of VEGF, surfactant proteins (SP-B and SP-C) and on alveolarisation in lung tissue of male and female pig fetuses. Methods: Fetuses from 10 sows were randomized to receive either both an intramuscular injection of the E2 receptor blocker ICI 182.780 and the P receptor blocker RTI 3021-022 (ICI + RTI, n = 5) or a placebo injection (n = 5) at 90 days of gestation (DOG, 115 = term). After delivery by cesarean section on 114 DOG, tissue of the left lingula of the piglet's lung (28 placebo, 26 ICI + RTI) was obtained to determine the mRNA expression of VEGF, SP-B and SP-C. Lungs from 15 placebo and 14 ICI + RTI group piglets were removed and alveolar counts performed. Results: The ICI + RTI group showed significantly lower SP-C mRNA expression and alveolar counts compared to the placebo group (p = 0.04 and 0.03, respectively). Diminished alveolarisation in the ICI + RTI group was mainly due to the reduction of alveolar counts in male piglets (p = 0.02). Within the placebo group VEGF and SP-B mRNA expression in male piglets were significantly lower compared to female piglets (p = 0.01 and 0.004, respectively). ICI + RTI treatment abolished this gender-related difference. Conclusion: Estradiol and P antagonism affected gender-related differences of key proteins for pulmonary function and development and especially in males was associated with diminished alveolarisation.
Cummings, James J. Nitric oxide decreases lung liquid production in fetal lambs. J. Appl. Physiol. 83(5): 1538-1544, 1997.-To examine the effect of nitric oxide on fetal lung liquid production, I measured lung liquid production in fetal sheep at 130 Ϯ 5 days gestation (range 122-137 days) before and after intrapulmonary instillation of nitric oxide. Thirtyone studies were done in which net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of radiolabeled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. To see whether changes in Jv might be associated with changes in pulmonary hemodynamics, pulmonary and systemic pressures were measured and left pulmonary arterial flow was measured by an ultrasonic Doppler flow probe. Variables were measured during a 1-to 2-h control period and for 4 h after a small bolus of isotonic saline saturated with nitric oxide gas (10 or 100%) was instilled into the lung liquid. Control (saline) instillations (n ϭ 6) caused no change in any variable over 6 h. Nitric oxide instillation significantly decreased Jv and increased pulmonary blood flow; these effects were sustained for 1-2 h. There was also a significant but transient decrease in pulmonary arterial pressure. Thus intrapulmonary nitric oxide causes a significant decrease in lung liquid and is associated with a decrease in pulmonary vascular resistance. In a separate series of experiments either amiloride or benzamil, which blocks Na ϩ transport, was mixed into the lung liquid before nitric oxide instillation; still, there was a similar reduction in lung liquid production. Thus the reduction in lung liquid secretion caused by nitric oxide does not appear to depend on apical Na ϩ efflux. pulmonary circulation; ion transport; birth transition; fetus
Respiratory Physiology & Neurobiology, 2008
We tested the hypothesis that postnatal exposure to progesterone or estradiol exerts distinct effects on respiratory control, apnea frequency, and on hypoxic ventilatory response (HVR). To this aim, we assessed breathing pattern using whole body plethysmography in normoxia and during a sustained hypoxic exposure (10% O2—30 min) in 10-day-old male rats raised by dams implanted with osmotic minipumps delivering either estradiol (E2, 7.0 μg day−1), estradiol + progesterone (E2 + P, 7.0 + 70 μg day−1) or vehicle (propylene glycol) at a regular flow rate throughout postnatal days 1–14. Compared to vehicle, E2 and E2 + P pups had a reduced ventilation, metabolic rate and rectal temperature. HVR was specifically increased in E2 + P pups compared to controls and E2 pups. On the contrary, both E2 and E2 + P pups did not reduced metabolism as much as controls during hypoxic exposure, and the decrease in rectal temperature was abolished. Surprisingly, E2 + P pups showed a dramatic elevation of sigh frequency, while progesterone (in E2 + P compared to E2 and Veh pups) reduced apnea frequency. These findings are relevant to better understand the role of placental steroids on respiratory and metabolic control during early development in rats, and could ultimately contribute to a better understanding of specific respiratory control disorders in preterm neonates, which are chronically deprived from placental steroids exposure.
Failure to Detect a Stimulatory Effect of Estradiol-17β on Ovine Fetal Lung Maturation
Pediatric Research, 1987
Animals. Fourteen pregnant ewes of mixed Western breed were studied between the 106th and 127th days of gestation. 145 ABSTRACT. It has been reported that estradiol-17P (E2) stimulates rat and rabbit fetal lung maturation; however, E2 was not directly administered to the fetus in these experiments. Therefore, we used the chronically instrumented fetal sheep to study the effects of 14 days of continuous E2 infusion on fetal lung maturation. Animals were instrumented on days 104-106 of gestation, then infused with either saline or E2 (100~g/day) from 111 to 127 days of gestation. Fetal plasma concentrations of E2, estrone, and cortisol, and tracheal fluid phosphatidylcholine:sphingomyelin ratios and phosphatidylcholine flux were measured daily in E2-infused (n = 8) and salineinfused (n = 6) control animals. At 127 days of gestation, fetuses were sacrificed and lung tissue samples obtained for biochemical and morphological analyses. Plasma E2 levels rose from 0.045 ± 0.001 (x ± SE) to 7.45 ± 5.31 ng/ml (p < 0.05) in E2-infused animals whereas levels remained < 0.06 ng/ml in saline-infused animals. Plasma estrone concentrations also were significantly elevated by E2 infusion. Plasma contisol concentrations increased from 0.58 ± 0.08 to 0.88 ± 0.40 Itg/dl in E2-treated fetuses during the last week of infusion whereas values in control animals were unchanged. The ratio of acetone-precipitated phosphatidylcholine to sphingomyelin and the flux of acetone-precipitated phosphatidylcholine in tracheal fluid were not affected by E2 infusion. Fetal lung tissue phospholipid content was also unaffected by E2 infusion. Furthermore, there was no consistent effect of E2 infusion on the histological structure of the fetal lung tissue as determined by morphometric methods. Therefore, we conclude that prolonged elevations in plasma E2 in the early to middle 3rd trimester of gestation, i.e., prior to 128 days of gestation, do not stimulate lung maturation in the intact ovine fetus. (Pediatr Res 22: 145-149, 1987) Abbreviations RDS, respiratory distress syndrome E2, estradiol-17P PC, phosphatidylcholine EI, estrone iv, intravenous RIA, radioimmunoassay DSPC, disaturated phosphatidylcholine S, sphingomyelin
Modulation of sodium transport in alveolar epithelial cells by estradiol and progesterone
Pediatric research, 2011
The effects of estradiol (E2) and progesterone (P) on alveolar epithelial Na+ transport were studied in isolated alveolar epithelial cells from 18- to 19-d GA rat fetuses, grown to confluence in serum-free media supplemented with E2 (0-1 μM) and P (0-2.8 μM). Short-circuit currents (ISC) were measured, showing an increase by E2 and P in a dose-dependent manner. The Na,K-ATPase subunits -α1 and -β1 were detected by Western blotting, but total expression was not significantly altered. Furthermore, all three epithelial Na+ channel (ENaC) subunits -α, -β, and -γ were detected, with trends toward a higher expression in the presence of E2 and P. Real-time PCR revealed an increase of α- and β-ENaC expression but no alteration of γ-ENaC. In addition, the mRNA expression of cystic fibrosis transmembrane conductance regulator (CFTR) and Na,K-ATPase-β1 subunit were elevated in the presence of E2 and P. Single-channel patch clamp analysis demonstrated putative highly selective and nonselective ...
Scientific Reports, 2021
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. During fetal development, lung epithelial cells actively secrete fluid, thereby filling the developing lung. Vectorial Cl − transport-driven pulmonary fluid accumulation supports lung growth by establishing an intra-pulmonary pressure that promotes cellular proliferation. Animal studies with intrauterine tracheal drainage as well as tracheal occlusion demonstrated the pivotal relationship between fluid accumulation and fetal lung development 1. A contribution of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) to this process has been suggested 2-4. More precisely, during fetal lung development CFTR expression exhibits a time-and tissuedependent expression pattern. The highest CFTR expression level was observed in the 1st and 2nd gestational trimester, while its expression gradually declines during the 3rd trimester 5,6. Epithelial cell proliferation was accelerated by Cftr over-expression in the pseudoglandular stage resulting in an enhanced lung growth 3. Prior to birth, the fetal lung fluid has to be removed to enable air breathing. Alveolar fluid clearance (AFC) is driven by epithelial Na + transport accomplished by epithelial Na + channels (ENaC) in the apical membrane compartment and the Na,K-ATPase in the basolateral membrane compartment of alveolar type II (ATII) cells. ENaC consist of three homologous subunits, α-, β-, and γ-ENaC 7 , and the Na-K-ATPase is composed of α 1-and β 1-subunits in ATII cells 8. Vectorial Na + transport establishes an osmotic driving force causing fluid absorption from the air spaces into the interstitium. In premature newborns a decreased AFC has been shown 9 , possibly due to a lower expression of epithelial Na + channels 10. In addition to surfactant deficiency, AFC insufficiency contributes to the development of the respiratory distress syndrome (RDS) 10. Importantly, a sex ratio of 1:1.7 11,12 was observed for the RDS incidence, with males developing RDS significantly more frequently compared with female infants of the same gestational age, raising male mortality 13. Up until now, male sex remains an independent risk factor for RDS development 11,12. We have previously shown sex-specific differences in alveolar Na + transport. Male sex was associated with lower Na + transport and reduced levels of the ENaC and Na-K-ATPase subunits in fetal distal lung epithelial (FDLE) cells 14. Na + transport in female cells was more responsive to female sex steroids
Sex-specific effects of sex steroids on alveolar epithelial Na+ transport
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2017
Alveolar fluid clearance mediates perinatal lung transition to air breathing in newborn infants, which is accomplished by epithelial Na+ channels (ENaC) and Na-K-ATPase. Male sex represents a major risk factor for developing respiratory distress, especially in preterm infants. We previously showed that male sex is associated with reduced epithelial Na+ transport, possibly contributing to the sexual dimorphism in newborn respiratory distress. This study aimed to determine sex-specific effects of sex steroids on epithelial Na+ transport. The effects of testosterone, 5α-dihydrotestosterone (DHT), estradiol, and progesterone on Na+ transport and Na+ channel expression were determined in fetal distal lung epithelial (FDLE) cells of male and female rat fetuses by Ussing chamber and mRNA expression analyses. DHT showed a minor effect only in male FDLE cells by decreasing epithelial Na+ transport. However, flutamide, an androgen receptor antagonist, did not abolish the gender imbalance, and...
Regulation of Postnatal Lung Development and Homeostasis by Estrogen Receptor
Molecular and Cellular Biology, 2003
Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor ␣ (ER␣) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ER is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ER gene (ER ؊/؊ ) revealed decreased numbers of alveoli in adult female ER ؊/؊ mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Plateletderived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ER ؊/؊ mice, and direct transcriptional regulation of these genes by ER was demonstrated. This suggests that estrogens act via ER in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ER as a previously unknown regulator of postnatal lung development and homeostasis.