Corticosteroid binding by fetal rat and rabbit lung in organ culture

Ballard, Philip L.; Ballard, Roberta A.; Gonzales, Linda K; Huemmelink, Raimund; Wilson, C. M.; Gross, Ian

doi:10.1016/0022-4731(84)90371-6

Cited by 35 publications

(14 citation statements)

References 29 publications

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“…Both GR binding activity and steady-state levels of GR mRNA were maximal in lung fibroblasts (and also in whole lung) at 19 d of gestation, 24 h before the maximal levels in distal airway epithelial cells. In whole lung, GR functional (hormone binding) activity increased progressively during late gestation, consistent with previously published data (17,18 in gestation in three divided doses, and it was given as the sodium phosphate salt in saline S.C. (39).…”

Section: Discussionsupporting

confidence: 90%

“…Kalinyak et al (16) reported a glucocorticoid induced decrease in GR mRNA levels in postnatal brain and liver, but no change in the corresponding fetal tissues. There are parallel increases in late gestation fetal lung in both glucocorticoid hormone concentration (1) and GR number (without any apparent change in affinity for ligand) (17,18), suggesting that glucocorticoids may not regulate fetal lung GR gene expression by a feedback down-regulatory mechanism.…”

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confidence: 99%

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Differential Regulation of Glucocorticoid Receptor Expression by Ligand in Fetal Rat Lung Cells

et al. 1995

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The glucocorticoid receptor (GR) mediates glucocorticoid stimulation of surfactant production by fetal mammalian lung. In many other tissues, glucocorticoids decrease expression of GR, thereby reducing responsiveness to these hormones. We therefore determined whether there is a similar effect of exogenous glucocorticoids on GR in fetal rat whole lung, and in the principal cell types involved in the stimulation of surfactant, the fibroblasts and the epithelial cells. The ontogeny of GR in late gestation lung differed between the two cell types, with maximal levels occurring in fibroblasts on gestational d 19, and on d 20 in epithelial cells. Administration of dexamethasone (1 mg/kg) to the mother on gestational d 18 or 19 (term = 22 d) increased specific GR binding activity in whole lung 24 h later. Furthermore, in vitro, incubation of cultured fibroblasts of gestational d 20 with 10K7 M cortisol increased GR immunoreactive protein and binding activity in a dose-and time-dependent manner, without affecting cellular levels of GR mRNA. However, identical treatment of d 20 distal airway epithelial cells was followed by decreased GR protein without significant change in cellular GR mRNA. Surfactant protein-A protein levels, taken as assessments of lung maturation, were increased in response to the same treatment. Our findings suggest that hormonal regulation of GR in fetal lung cells occurs at a posttranscriptional level, and is cell-specific. In the context of substantial increases in circulating glucocorticoid concentrations during late gestation, these findings may be of physiologic importance to the biochemical maturation of the antenatal lung. (Pediatr Res 38: [506][507][508][509][510][511][512] 1995) Abbreviations GR, glucocorticoid receptor FBS, fetal bovine serum FPF, fibroblast-pneumocyte factor MEM, minimal essential medium SP-A, surfactant protein-A Glucocorticoids accelerate the onset of mature levels of surfactant synthesis by fetal mammalian lung (1-3) via the classic GR mechanism (1, 2, 4-9). However, in many tissues, glucocorticoids decrease GR expression, thereby decreasing tissue responsiveness to glucocorticoid stimulation. The effect of glucocorticoids on GR in late gestation fetal lung around the time of the onset of augmented surfactant production is incompletely understood.Administration of glucocorticoids decreases GR mRNA (10) and GR protein (1 1) in several adult rat organs, including lung. In various cell lines, glucocorticoids lower GR number by decreasing GR transcription rates without altering affinity for ligand (12,13). However, it is recognized that the response of GR mRNA steady-state levels to glucocorticoid treatment can

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

Differential Regulation of Glucocorticoid Receptor Expression by Ligand in Fetal Rat Lung Cells

et al. 1995

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“…The hormone was removed from some cultures 24 h later (day 2) by changing the culture medium three times at 2-h intervals. Cortisol was chosen for these experiments because of its relatively fast dissociation from glucocorticoid receptors (29). Removal of cortisol blocked any further increase in SP-C mRNA content and diminished the response for SP-B mRNA; by day 4-5 levels in cultures treated briefly with cortisol were similar to control values.…”

Section: Resultsmentioning

confidence: 99%

“…We found similar results in earlier studies with human lung examining the rate of choline incorporation into phosphatidylcholine (24). The stimulatory effect ofcortisone, which has no intrinsic glucocorticoid activity, was not unexpected, since lung tissue contains 1 lj3-hydroxysteroid dehydrogenase which catalyzes interconversion of cortisone and cortisol (29,31).…”

Section: Resultsmentioning

confidence: 99%

Regulation of messenger RNAs for the hydrophobic surfactant proteins in human lung.

Liley¹,

White²,

Warr³

et al. 1989

J. Clin. Invest.

163

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The pulmonary surfactant proteins 000 D) and SP-C (4,000 D) accelerate surface film formation by surfactant phospholipids. We used cDNA probes to examine regulation of these proteins in human fetal lung. The mRNAs were detectable at 13 wk gestation and increased to -50% (SP-B) and -15% (SP-C) of adult levels at 24 wk. The mRNAs were detected only in lung of 11 dog tissues examined. When human fetal lung was cultured as explants without hormones, SP-B mRNA increased and SP-C mRNA decreased. Exposure for 48 h to glucocorticoids, but not other steroids, increased both SP-B mRNA (-4-fold) and SP-C mRNA (-30-fold) vs.controls. Half-maximal stimulation occurred with 1 nM dexamethasone and 300 nM cortisol for SP-B mRNA and at threeto fivefold higher concentrations for SP-C mRNA. Both stimulation and its reversal on removal of hormone were more rapid for SP-B than for SP-C. Terbutaline and forskolin increased SP-B mRNA but not SP-C mRNA. Levels of both mRNAs were much higher in type II cells than fibroblasts prepared from explants. Thus, the genes for SP-B and SP-C are expressed in vivo before synthesis of both SP-A (28,000-36,000 D) and surfactant lipids. Glucocorticoid induction of SP-B and SP-C mRNAs in type II cells appears to be receptor mediated but may involve different mechanisms.

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“…This becomes important when evaluating fetal maturation where expression levels can be extremely low because of the immature state of the developing organ. Furthermore, the biggest advantage of the chosen markers is that the protein levels of these markers as a function of gestation in control fetal rat lung are available in the literature (Ballard et al, 1984;Schellhase et al, 1989;Shimizu et al, 1991). By establishing a mathematical relationship between the measured message and protein data from the literature in the control group, the behavior of the marker proteins in the DEX-treated animals can be predicted.…”

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confidence: 99%

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: II. Temporal Patterns of Gene Expression in Fetal Rat Lung

Samtani

Pyszczynski²,

DuBois³

et al. 2005

J Pharmacol Exp Ther

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Our previous report described the temporal steroid patterns during pharmacokinetic (PK) studies with dexamethasone (DEX) where doses of six 1 mol/kg injections were given during gestational ages 18 to 20 days in rats. DEX PK was used in conjunction with the endogenous corticosterone profile to understand the regulation of fetal lung pharmacodynamics (PD). Expression of the glucocorticoid receptor (GR) and surfactant proteins A and B mRNA were chosen as lung maturational markers. GR seemed to be insensitive to the circulating glucocorticoids, indicating that unlike the adult situation, GR was not under negative feedback control of its ligand. Surfactant protein B exhibited ϳ400-fold induction in control fetal lung during the last days of gestation, and the inductive effect was even greater in the treatment group. Surfactant protein A displayed ϳ100-fold induction in control fetal lung during late gestation. However, the treatment group exhibited biphasic stimulatory and inhibitory effects for surfactant protein A. The inhibitory effect indicated that the chosen dosing scheme for DEX was not an optimal regimen. These data were used to determine by simulation the DEX regimen that would reproduce the temporal pattern of lung maturation observed in control animals. PK/PD modeling indicated that maintaining steroid exposure at approximately twice the equilibrium dissociation constant for the steroid/receptor interaction should produce optimal stimulation of both surfactant proteins. The simulations illustrate that administering smaller quantities of steroids over extended periods that produce sustained steroid exposure might be the optimal approach for designing dose-sparing antenatal corticosteroid therapy.Glucocorticoids (GR) accelerate fetal lung maturation in almost every animal species studied (Ballard, 1986). Glucocorticoids are clearly involved in normal fetal lung maturation because knockout animals for either GR or the glucocorticoid precursor corticotrophin releasing hormone die at birth because of lack of lung development (Cole et al., 1995;Muglia et al., 1995). The importance of the steroid/receptor interaction is exemplified by the fact that the corticotrophin releasing hormone knockouts are rescued by glucocorticoid treatment, whereas the GR knockouts are not.Glucocorticoids induce lung maturation by stimulating the production of pulmonary surfactant (Kotas and Avery, 1971). Lung surfactant, composed of glycerophospholipids and proteins, helps to reduce the surface tension at the alveolar air-liquid interface. Enzymes involved in glycerophospholipid synthesis as well as surfactant proteins are under the transcriptional control of glucocorticoid-bound receptor molecules. Evidence supporting GR-gene-mediated process regulating fetal lung maturation has been reviewed by Ballard and Ballard (1995).In spite of the rich literature concerning glucocorticoidinduced fetal lung maturation, most studies have been performed using isolated cells and explant cultures of fetal lung. Only sparse information is a...

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Corticosteroid binding by fetal rat and rabbit lung in organ culture

Cited by 35 publications

References 29 publications

Differential Regulation of Glucocorticoid Receptor Expression by Ligand in Fetal Rat Lung Cells

Differential Regulation of Glucocorticoid Receptor Expression by Ligand in Fetal Rat Lung Cells

Regulation of messenger RNAs for the hydrophobic surfactant proteins in human lung.

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: II. Temporal Patterns of Gene Expression in Fetal Rat Lung

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