Yue Ning

Glucocorticoid regulation of surfactant components in immature lambs.

To assess effects of dose and duration of glucocorticoid exposure on maturation of the fetal lung, we administered single or multiple doses of betamethasone (0.5 mg/kg im) to pregnant sheep for 2 or 21 days before preterm delivery at 125 days of gestation. Lung function (compliance, lung volume at 40 cmH2O pressure, and ventilatory efficiency index) was increased after two to four weekly doses of glucocorticoid (2.5- to 4-fold increase) and after 48 h of exposure (1.4- to 2.3-fold). Total protein of lavage fluid decreased similarly with three doses, four doses, and 48 h of treatment. In lambs with long-term exposure to betamethasone, there was a similar, dose-dependent increase in concentrations of saturated phosphatidylcholine and surfactant proteins A (SP-A) and B (SP-B) (maximal 2- to 3-fold in tissue and 10- to 15-fold in lavage fluid). Levels of SP-A and SP-B were closely correlated in lavage fluid. In animals treated for 48 h, only tissue SP-B was increased (2.7-fold). We conclude that 48 h of glucocorticoid treatment improves lung function in the premature lamb without a detectable increase in lavage surfactant components and that longer exposure to antenatal glucocorticoid increases surfactant lipid and proteins in a coordinated fashion. The enhanced response with repetitive dosing indicates that the process of glucocorticoid-induced lung maturation is either reversible and/or gestational age dependent.

Surfactant Function and Composition in Premature Infants Treated With Inhaled Nitric Oxide

OBJECTIVES. We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition. METHODS. As part of the Nitric Oxide Chronic Lung Disease Trial of inhaled nitric oxide, we examined surfactant in a subpopulation of enrolled infants. Tracheal aspirate fluid was collected at specified intervals from 99 infants with birth weights <1250 g who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Large-aggregate surfactant was analyzed for surface activity with a pulsating bubble surfactometer and for surfactant protein contents with an immunoassay. RESULTS. At baseline, before administration of study gas, surfactant function and composition were comparable in the 2 groups, and there was a positive correlation between minimum surface tension and severity of lung disease for all infants. Over the first 4 days of treatment, minimum surface tension increased in placebo-treated infants and decreased in inhaled nitric oxide–treated infants. There were no significant differences between groups in recovery of large-aggregate surfactant or contents of surfactant protein A, surfactant protein B, surfactant protein C, or total protein, normalized to phospholipid. CONCLUSIONS. We conclude that inhaled nitric oxide treatment for premature infants at risk of bronchopulmonary dysplasia does not alter surfactant recovery or protein composition and may improve surfactant function transiently.

Plasma Thyroid Hormones in Premature Infants: Effect of Gestational Age and Antenatal Thyrotropin-Releasing Hormone Treatment

Thyroid hormones are important for both perinatal adaptation and long-term psychomotor development; however, there is limited information on the effects of extreme prematurity and antenatal TSH-releasing hormone (TRH) treatment on pituitary-thyroid function. In this study we assayed plasma triiodothyronine (T3) and TSH in infants who were part of a collaborative trial of antenatal maternal TRH therapy. Within the control population (n = 166), infants of 24-28-wk and 28-32-wk gestational age had comparable levels of T3 (0.94 and 1.06 nmol/L, respectively) and TSH (5.7 and 7.2 mU/L) at birth, but the increases at 2 h and subsequent T3 levels were less in the 24-28 wk versus 28-32-wk gestation infants. In the TRH-treated group (n = 131), T3 was lower in the first day for infants delivered 7-72 h after antenatal TRH compared with control infants. TSH at birth was ∼3.5-fold greater for infants delivered at 0-6 h after the last TRH dose compared with the control group and was suppressed in infants delivering at 7-36 h. T3 and TSH levels were not different between control and TRH-treated groups at 3-28 d of age. In TRH stimulation tests on d 28, control and TRH-treated groups had similar peak levels of TSH and incidence of exaggerated response (TSH ≥ 35 mU/L). We conclude that extremely premature infants have a reduced postnatal surge in TSH and T3 and maintain lower T3 concentrations, probably reflecting tertiary hypothyroidism. The stimulatory and suppressive effects of antenatal TRH treatment observed at birth are transient and do not affect pituitary-thyroid responsiveness at 28 d of age.

Transcriptional regulation of surfactant proteins SP-A and SP-B by phorbol ester

Phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) activate protein kinase C and have been previously shown to down-regulate surfactant proteins SP-A and SP-B in H441 adenocarcinoma cells. We used H441 cells and human fetal lung to further study the mechanism of TPA action and to examine physiologic relevance. In H441 cells, TPA (10 nM) treatment for 24 h decreased SP-A mRNA content to approximately 5% of control cells, with half-maximal effect at approximately 0.5 nM, and reduced SP-A gene transcription rate to 28% of control after 8 h exposure. In cells cultured in the presence of dexamethasone, which increases the low basal level of SP-B expression, TPA decreased both SP-B mRNA content (approximately 8% of control) and rate of transcription (7% of control). In cultured human fetal lung explants, TPA decreased SP-A and SP-B protein and mRNA in a time- and dose-dependent fashion, with half-maximal effect on mRNAs at approximately 3 nM and approximately 50% inhibition after 24 h of exposure, and similarly reduced SP-A and SP-B gene transcription (approximately 55% of control at 8-24 h). We conclude that TPA acts primarily at the level of gene transcription to down-regulate both SP-A and SP-B in H441 and fetal lung cells, and we speculate that inflammatory and other agents that act through PKC may modulate expression of the surfactant proteins and alter surfactant function in vivo.

Down-Regulation of TGF-β and Expression of Surfactant Protein Genes in Type II Epithelial Cells of Human Fetal Lung

Down-Regulation of TGF-β and Expression of Surfactant Protein Genes in Type II Epithelial Cells of Human Fetal Lung

Plasma Thyroid Hormone Concentrations in Premature Infants and Effect of Thyrotropin Releasing Hormone (TRH) |[dagger]| 954

Plasma Thyroid Hormone Concentrations in Premature Infants and Effect of Thyrotropin Releasing Hormone (TRH) † 954

Adenovirus-mediated Transduction of Type 2 Alveolar Cells to Express Recombinant Surfactant Protein-B (rSP-B) • 1659

Adenovirus-mediated Transduction of Type 2 Alveolar Cells to Express Recombinant Surfactant Protein-B (rSP-B) • 1659

Lipogenic Enzymes and Surfactant Proteins in Fetal Sheep Lung Have Different Ontogenic Patterns. 272

Functional maturation of fetal sheep lung is enhanced by glucocorticoids(GC), but ontogeny and hormonal regulation of enzymes involved in surfactant production have not been studied. Activities of two lipogenic enzymes (fatty acid synthetase, FAS; cholinephosphate cytidylyltransferase, CYT) increase during development and are induced by GC in fetal lung of 2 species (rat, human) in vivo and/or in vitro. We studied these enzymes and surfactant proteins A and B (SPA, SPB) in lungs (n =15) from sheep fetuses of ≈60d gestation to ≈10d postnatal. FAS protein content (western blot), FAS activity (14Cmalate incorp. into fatty acid), CYT activity(14CCDPcholine formed), and SPA and SPB contents (immunodot assay) were determined. FAS specific activity was maximal at ≈120d (0.36±0.05 nmol/min/mg prot), dropping by 75% at term (≈148d, p<0.01); western analysis confirmed a similar decline in FAS protein content. CYT activity in both soluble and particulate fractions was highest at ≈90d(0.36±0.03 and 0.19±0.04 nmol/min/mg prot., respectively), decreasing by 50% at term (p<0.05). Tissue protein/DNA ratio was constant at all ages. Tissue SPA and SPB were undetectable at 60d or 90d, present at 125d gestation, and increased 510 fold by term (p<0.05). To assess shortterm GC effect, fetuses were treated with betamethasone (0.5 mg/kg) via maternal or intraamniotic injection 48h prior to delivery at 125d gestation. Lung compliance increased with treatment (≈50%, p<0.05), but FAS and CYT activities remained constant. We conclude that FAS and CYT enzymes are not developmentally correlated with other markers of surfactant system maturation(increased DPPC, SPA, SPB) in fetal sheep lung, nor responsive to short GC exposure. We hypothesize that either de novo lipogenic activity in fetal sheep lung is adequate by early third trimester or that circulationderived fatty acid is the primary source for surfactant lipid synthesis in the fetal sheep.