Sex hormone metabolism in lung development and maturation (original) (raw)
Dihydrotestosterone Inhibits Fetal Rabbit Pulmonary Surfactant Production
Journal of Clinical Investigation, 1982
A B S T R A C T Males have a higher morbidity and mortality for neonatal respiratory distress syndrome (RDS) than females, and respond less well to hormone therapy designed to prevent RDS by stimulating fetal pulmonary surfactant production. We have shown that male fetuses exhibit delayed production of pulmonary surfactant. We tested the hypothesis that the sex difference in fetal pulmonary surfactant production is under hormonal control. Pulmonary surfactant was measured as the saturated phosphatidylcholine/sphingomyelin ratio (SPC/S) in the lung lavage of fetal rabbits at 26 d gestation. There was an association between the sex of neighboring fetuses and the SPC/S ratio of the female fetuses, such that with one or two male neighbors, respectively, females had decreasing SPC/ S ratios (P < 0.05). We injected dihydrotestosterone (DHT) into pregnant does from day 12 through day 26 of gestation in doses of 0.1, 1.0, 10, and 25 mg/d, and measured the SPC/S ratio in fetal lung lavage on day 26. In groups with the normal sex difference in fetal serum androgen levels (controls, 0.1 mg DHT/d) the normal sex difference in the SPC/S ratio was also present (females> males, P = 0.03). In the 1-mg/d group there was no sex difference in androgen levels and the sex difference in the SPC/S ratio was also eliminated as the female values were lowered to the male level. Higher doses of DHT (10, 25 mg/d) further reduced the SPC/S ratios. We injected the anti-androgen Flutamide (25 mg/d) from day 12 through day 26 of gestation. This treatment eliminated the normal sex difference in the lung lavage SPC/S ratio by increasing the male ratios to that of the females. We conclude that androgens inhibit fetal pulmonary surfactant production. An understanding of the mechanism of the sex difference in surfactant production may allow development of therapy that is as effective in males as in females for preventing RDS.
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
Sex Differences in Fetal Rabbit Pulmonary Surfactant Production
Pediatric Research, 1981
New Zealand White rabbit does were mated between 0900 and than females at concurrent gestations. Recent evidence in humans 1200 hr and sacrificed between these hours on day 24, 26, 28, or has linked fetal sex with differences in amniotic fluid indices of 30 of gestation (day 0 = day of mating; term = 31 days). Does lung maturation. We tested the hypothesis that the late gestation were sacrificed with an intravenous injection of pentobarbital (180 surge in pulmonary surfactant production occurs later in the male mg). The uterus was then exposed, and the fetuses were sacrificed fetus than in the female fetus in the rabbit model. We measured with 30 mg of pentobarbital intraperitoneally, injected through saturated phosphatidylcholine and total phosphatidylcholine in the uterine wall. AF was obtained on each fetus by puncturing the lung lavage a t 26, 28, and 30 days gestation and in amniotic fluid fetal membranes after dissecting away the uterine wall. Each fetus a t 24,26,28, and 30 days gestation (term = 31 days). The saturated was weighed and then tracheostomized, and LL was obtained by phosphatidylcholine/sphingomyelin ratios were 158 and 55% lavaging the lungs with 5 X 0.5 ml of 0.9% iced NaCl solution. We higher in female fetal lung lavage a t 26 and 28 days, respectively, were unable to obtain reliable LL samples on 24 day gestation and 75% higher in amniotic fluid at 28 days (P < 0.05). The total fetuses. Bloody LL or AF samples were discarded. Fetal sex was phosphatidylcholine/sphingomyelin ratios were 39% higher in fe-determined by inspection of the gonads and confirmed histologimale fetal lung lavage and 35% higher in female amniotic fluid a t cally.
The Journal of Steroid Biochemistry and Molecular Biology, 2009
Many genes involved in the peripheral metabolism of androgens, including hydroxysteroid (17) dehydrogenases (HSD17B) 2 and 5, steroid 5␣ reductase 1, and 3␣-HSD, are expressed in the developing lung. Because lung development is delayed by androgens and pathologies related to lung immaturity are major concerns for preterm neonates, we are interested in the elucidation of the androgen metabolism in developing lung. In the present report we have identified the cell types expressing HSD17B2 (testosterone into androstenedione) and androgen receptor in normal male and female mouse developing lung between the gestation days 15.5 and 17.5. In situ hybridization and immunohistochemistry revealed that HSD17B2 is expressed in epithelial cells of respiratory and conducting zones, and in mesenchymal cells. The androgen receptor protein was observed in the same cell types that HSD17B2, and in ␣-smooth muscle actin-positive cells surrounding arteries. No difference was observed for the location of HSD17B2 and androgen receptor expression at any time points studied, or according to sex. Taken together, our results are in concordance with the hypothesis that in mouse fetal lungs the level of androgen receptor occupancy is finely tuned by local HSD17B2 expression.
Fetal Lung Liquid: A Major Determinant of the Growth and Functional Development of the Fetal Lung
Clinical and Experimental Pharmacology and Physiology, 1995
1. During fetal life the lung develops as a liquid-filled organ. This liquid is produced by the fetal lung and leaves via the trachea from where it is either swallowed or enters the amniotic sac. Fetal lung liquid plays a crucial role in the growth and development of the lungs by maintaining them in a distended state. It is now recognized that the retention of liquid within the future airways is required to maintain the lungs at an appropriate level of expansion in order to stimulate their growth. Indeed, it is likely that most, if not all, of the conditions and malformations that lead to inadequate growth of the fetal lung do so by reducing the volume of lung liquid and hence the degree of lung expansion. 2. The volume of fetal lung liquid is principally regulated by the resistance to lung liquid efflux through the fetal upper airway and by the presence of diaphragmatic activity associated with fetal breathing movements (FBM). During non-breathing periods, the relatively high resistance offered by the upper airway to the efflux of lung liquid opposes the loss of liquid from the lung, thereby maintaining fetal lung expansion. During episodes of FBM, when the larynx is actively dilated and the resistance to lung liquid efflux is reduced, lung liquid leaves the lungs at an increased rate. However, selective inhibition of diaphragmatic muscle activity in the foetus leads to a reduction in lung liquid volume, rather than an increase. This finding indicates that during periods of FBM, rhythmical contractions of the diaphragm retard the loss of lung liquid and help to maintain lung expansion when the upper airway resistance is reduced. It is now apparent that the maintenance of lung expansion by FBM is the basis for their role in promoting fetal lung growth. 3. Successful transition from intra-uterine to extra-uterine life is dependent upon the clearance of liquid from the fetal lungs at the time of birth so that the lungs may effectively function as an organ of gas exchange. It is generally considered that, at the time of birth, increased circulating levels of the stress-related hormones, adrenaline and arginine vasopressin
Journal of Clinical Investigation, 1985
A sexual dimorphism in fetal pulmonary maturation has been described in which the female fetal lung produces surfactant earlier in gestation than the male fetal lung. This is felt to be related to the increased incidence in male newborns of the Respiratory Distress Syndrome. Dihydrotestosterone will delay surfactant production in the female fetus, and a relationship between fetal sexual differentiation and fetal lung maturation has been proposed. We hypothesized that the dimorphism in fetal surfactant production is dependent on androgen receptor function. We measured phosphatidylcholine (PC), saturated phosphatidylcholine (SPC), and sphingomyelin (S) in the amniotic fluid of fetal mice of the mouse model of testicular feminization (Tfm mouse). In this model, male carriers of the X-linked Tfm gene have no functional androgen receptors. The mean amniotic fluid phosphatidylcholine to sphingomyelin ratio (PC/S ratio) was 28% higher in females than in normal males, and the amniotic fluid PC/S ratio of the Tfm male fetuses was the same as the females. The ratio of amniotic fluid saturated phosphatidylcholine to sphingomyelin (SPC/S ratio) was lowest in males, intermediate in females, and highest in Tfm males. A significant relationship between the fetal groups and the amniotic fluid SPC/S ratio was identified by analysis of variance. There were no differences in the whole lung phospholipid content between the three groups.