Glucocorticoids and Thyroid Hormones Stimulate Biochemical and Morphological Differentiation of Human Fetal Lung in Organ Culture*

Abstract

We characterized the stimulatory effects of both glucocorticoids and thyroid hormones on the surfactant system in human fetal lung. Synthesis of phosphatidylcholine (PC) and morphology were examined in explant cultures (15-24 weeks gestation) maintained 1-7 days in serum-free Waymouth's medium in a 95%-air-5% CO2 atmosphere. Control explants (no hormones) had the same rate of choline incorporation into PC between 1 and 7 days, but a significant increase in tissue PC content [82 +/- 21%, (+/- SEM), day 6 vs. 1], consistent with slow turnover of PC. [3H]Choline incorporation was stimulated 36%, 137%, and 192% by T3 (2 nM), dexamethasone (Dex; 10 nM), and T3 plus Dex, respectively, after 6 days of exposure (optimal response) compared to 19%, 38%, and 84% after 2 days of exposure. Thus, a supra-additive response occurred in the presence of both hormones and was greater at a shorter exposure time. Dex increased the percent saturation of newly synthesized PC (28.9 +/- 0.9% vs. 17.8 +/- 0.8% for control), but T3 did not, whereas both hormones increased tissue PC content (74.4 +/- 7.3% and 18.7 +/- 7.8% increase vs. control, respectively). Pulse-chase experiments with [3H]choline suggest that remodeling of unsaturated PC to saturated PC occurred during culture and was stimulated by Dex. Incorporation of [3H]acetate and [3H]glycerol into PC was stimulated by Dex (830% and 77%, respectively), but not by T3; the distribution of incorporated radioactivity among phospholipids was changed by Dex (increased counts per min into PC and phosphatidylglycerol with acetate and glycerol, respectively), but not by T3. Half-maximal stimulation of choline incorporation occurred at concentrations of Dex (2.1 nM) and T3 (0.03 nM) that are similar to the Kd values for receptor binding (5 and 0.05 nM, respectively). The relative potencies of thyroid hormones were T3 greater than T4 greater than rT3, and for corticosteroids, Dex much greater than corticosterone greater than 11-dehydrocorticosterone = cortisol greater than cortisone. Stimulation by either T3 or cortisol was reversed within 24-48 h of hormone removal. Initial treatment of explants with Dex enhanced the subsequent response to T3, but not vice versa. Culture for 4-5 days in the absence of hormones produced some morphological maturation of the epithelial cells, whereas treatment with T3 plus Dex markedly increased the number and size of lamellar bodies in epithelial cells, caused extensive proliferation of apical microvilli, and reduced glycogen deposits. Our findings are consistent with receptor-mediated stimulation of surfactant synthesis in human lung by both glucocorticoids and thyroid hormones.(ABSTRACT TRUNCATED AT 400 WORDS)

The influence of amino-acid supplementation, gestational age and time on thyroxine levels in premature neonates

“…[4][5][6] Normal thyroid hormone levels promote normal growth and development in the fetus and prematurely born neonates. [7][8][9][10][11] The data provided in this article are taken from a randomized, double-blind clinical trial, which examined whether increased intravenous amino-acid supplementation would improve growth. In this trial, it was hypothesized that increased amino-acid supplementation would improve growth and well being and that normalization of serum amino acids would increase thyroxine levels.…”

Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

“…These paradoxical effects of GCs on human fetal membranes and placenta are believed to be part of the positive feedback loops involved in human parturition (Whittle et al 2001). It is well known that GCs are indispensable hormones for cell differentiation and organ maturation in the fetus (Gonzales et al 1986), but excess of GCs impedes fetal growth (Shams et al 1998. In consideration of all these above effects of GCs in pregnancy, understanding the metabolism of GCs by 11b-HSD could undoubtedly have an important impact on the outcome of pregnancy.…”

Neonatal Thyrotoxicosis and Persistent Pulmonary Hypertension Necessitating Extracorporeal Life Support

“…10,23,24 Triiodothyronine augments phosphatidylcholine and thus surfactant production by increasing choline phosphate cytidyltransferase activity. 25 Thyrotoxicosis, however, reduces critical surfactant protein production through 2 indirect mechanisms.…”