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Fetal Lung Maturation in Estrogen-Deprived Baboons

Department of Physiological Sciences (G.J.P.), Eastern Virginia Medical School, Norfolk, Virginia 23501-1980; Department of Pediatrics (P.L.B.), University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; and Departments of Obstetrics/Gynecology/Reproductive Sciences and Physiology (E.D.A.), Center for Studies in Reproduction, University of Maryland School of Medicine, Baltimore, Maryland 21201-1509

Address all correspondence and requests for reprints to: Gerald J. Pepe, Ph.D., Department of Physiological Sciences, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, Virginia 23501-1980. E-mail: pepegj{at}evms.edu.

	Abstract

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We have previously shown that estrogen plays a central integrative role in regulating key aspects of fetal-placental development and that inhibition of estrogen production during the second half of baboon pregnancy suppressed fetal adrenal function. Because maturation of the fetal lung is dependent on cortisol of fetal adrenal origin, the current study determined whether lung development and expression of surfactant proteins (SPs) A and B were altered at term in estrogen-deprived baboons. Fetal lungs were obtained on d 100, 165, and 175 of gestation (term = d 184) from untreated baboons and on d 165 from animals treated daily during the second half of pregnancy either with the aromatase inhibitor CGS 20267 alone or with CGS 20267 and estradiol benzoate. Umbilical venous estradiol levels were suppressed by more than 95% by CGS 20267 and elevated by CGS 20267 and estrogen. Although umbilical serum cortisol levels were also suppressed by 35% by CGS 20267, cortisol levels in the fetal lung of estrogen-suppressed baboons were similar to values in untreated animals. Immunocytochemistry demonstrated that CGS 20267 treatment did not alter fetal lung expression of the 11ß-hydroxysteroid dehydrogenase enzyme-1 enzyme catalyzing reduction of cortisone to cortisol. However, immunocytochemical expression of the 11ß-hydroxysteroid dehydrogenase enzyme-2 catalyzing oxidation of cortisol to cortisone appeared lower in lungs of estrogen-deprived fetuses and restored to normal by CGS 20267 and estrogen. SP-A levels in fetal lungs of untreated baboons were increased 16- to 20-fold between d 100 and d 165–175 of gestation in untreated baboons and baboons treated with CGS 20267 or CGS 20267 and estrogen. Similarly, SP-B levels in fetal lungs of untreated baboons were increased 10-fold between d 100 and d 165–175 of gestation in untreated baboons and baboons treated with CGS 20267 or CGS 20267 and estrogen. Moreover, in estrogen-suppressed baboons, as in untreated animals, the fetal lung continued to grow and exhibited normal alveolarization on histology. We conclude that development of the primate fetal lung can occur in utero in baboons in which fetal serum cortisol levels have been suppressed by the relative absence of estrogen perhaps because of the ability of the lung to coordinate local production of cortisol.

	Introduction

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OUR LABORATORIES HAVE shown that estrogen regulates the expression and subcellular localization of the 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSD)-1 and -2 within the syncytiotrophoblast (1), which causes increased transplacental oxidation of cortisol to cortisone during the second half of baboon gestation (2, 3). Consequently, this resulted in decreased maternal secretion of cortisol into the fetus, which resulted in enhanced fetal pituitary ACTH secretion (4) and maturation of de novo cortisol production by the baboon fetal adrenal gland (5, 6). Recently we showed that inhibition of estrogen production by administration of an aromatase inhibitor during the second half of baboon pregnancy suppressed 11ß-HSD-1 and -2 expression and compartmentalization within the syncytiotrophoblast, which we proposed would result in continued secretion of maternal cortisol into the fetus and thus inhibition of fetal adrenal maturation (7). Indeed, the activity and mRNA levels of the 3ß-hydroxysteroid dehydrogenase-isomerase enzyme catalyzing cortisol synthesis in the transitional zone of the fetal adrenal were significantly decreased at term in baboons in which the estrogen-dependent induction of placental cortisol oxidation was prevented by inhibition of the action (8) or the synthesis of estrogen (Albrecht, E. D. and G. J. Pepe, unpublished observations). It is well established that fetal adrenal cortisol is essential to activity and coordinated production of surfactant in and thus maturation of the fetal lung (9, 10, 11, 12, 13). Development of the baboon fetal lung has been extensively studied by Coalson et al. (14), who showed that cell-specific expression of the surfactant proteins A, B, and C increased markedly after d 120–140 of gestation, the same interval during which estrogen-dependent maturation of the placental-fetal pituitary-adrenocortical axis occurs (6). As in the human, the baboon genome contains two surfactant protein (SP)-A genes (15), which encode SP-A proteins that are essentially identical and are developmentally regulated in part by cAMP and glucocorticoid (16).

Collectively, on the basis of these observations, it is possible that fetal lung development would also be compromised in primates in which fetal pituitary adrenocortical maturation was suppressed by estrogen deprivation. The current study was designed, therefore, to determine whether development and expression of surfactant proteins by the fetal lung are altered in baboons in which fetal adrenal maturation was prevented by suppressing estrogen.

	Materials and Methods

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Animals

Fetal lungs were obtained on d 100 (n = 9), 160–168 (n = 8), and 170–175 (n = 8) of gestation (term = d 184) from untreated baboons and on d 160–165 of gestation from baboons treated daily beginning on d 60 (n = 6) or 100 (n = 6) with the aromatase inhibitor CGS 20267 (Letrozol, 4,4''-[1,2,4,-triazol-1yl-methylene]bis-benzonitrite, Novartis Pharma AG, Basel, Switzerland) administered to the mother sc (1–2 mg/d per milliliter sesame oil). Samples were also collected on d 160–165 from baboons treated with CGS 20267 (2 mg/d) and estradiol-benzoate beginning on d 60 (n = 4) or 100 (n = 3) of gestation at doses (1.0–2.0 mg/d per milliliter sesame oil) designed to replicate the normal pattern of serum estradiol as described previously (17). On d 100 or 165/175 of gestation, baboons were anesthetized with isoflurane-nitrous oxide, maternal saphenous and umbilical venous samples (3–6 ml) collected, the fetus delivered and euthanized with an overdose of sodium pentobarbital. The entire fetal lung was removed, weighed, and sections from each lobe stored in liquid nitrogen or fixed in 10% phosphate-buffered formalin. Animals were cared for and used strictly in accordance with USDA regulations and the NIH Guide for the Care and Use of Laboratory Animals (PHS publication no. 86-23, 1985). The experimental protocol was approved by the Institutional Animal Care and Use Committees of the Eastern Virginia Medical School and the University of Maryland School of Medicine.

SP-A and SP-B protein in fetal lung

The content of SP-A and SP-B in lung tissue was determined essentially as described by Ballard et al. (13). Briefly, aliquots of lung sonicate were serially diluted in PBS (pH 7.4, Sigma, St. Louis, MO) and applied to nitrocellulose membrane in a multiwell dot-blot apparatus under negative pressure (13). Each assay contained an equal number of samples from each treatment group to minimize interassay variability. Typically, six dilutions of each sample were applied along with 2-fold serial dilutions of pooled lung samples from animals of d 170–175 gestation, which served as an internal standard. Membranes were blocked with a 5% milk protein solution, washed, and then exposed to rabbit polyclonal antibodies to human SP-A or human SP-B diluted 1:10,000 or 1:5,000, respectively (18, 19). Secondary antibody conjugated with horseradish peroxidase was used along with enhanced chemiluminescent reagents and the blots exposed to x-ray film for varying times to provide signals for each sample within the linear range (13). The x-ray films were analyzed by scanning densitometry and arbitrary densitometric units plotted against the log of the protein concentration determined by methods of Bradford (20). The concentration of surfactant protein for each sample was calculated from the linear portion of the dose-response curve and the data from all groups then normalized to values from the pooled sample of late gestation baboon lung and expressed as a percentage of the level at term. Specificity of these antibodies for use in baboon lung specimens was confirmed in preliminary studies demonstrating extensive reduction in signal using antibodies preabsorbed with respective purified surfactant protein.

Histology and 11ß-HSD-1 and -2 immunocytochemistry

Paraffin-embedded sections of baboon fetal lungs were stained with hematoxylin and eosin and examined by light microscopy. The immunocytochemical detection of 11ß-HSD-1 and -2 proteins in baboon fetal lung was determined essentially as described previously (1, 7). Briefly, peroxidase-blocked sections (4 µm) were microwaved for 15 min in sodium citrate buffer (pH 6.0; Sigma), cooled (30 min), washed in PBS, blocked (30 min) in 5% normal goat serum (Vector Laboratories, Inc., Burlingame, CA) and incubated overnight at 4 C with rabbit primary antibodies to 11ß-HSD-1 or -2 diluted 1:2000 in 5% normal goat serum. After washing, sections were incubated with biotinylated antirabbit IgG (DAKO Corp., Carpenteria, CA) and biotin detected with an avidin peroxidase kit (Vector Laboratories, Inc.). After chromogen development, sections were washed, mounted, and photographed.

RIAs

The levels of estradiol and cortisol in maternal and umbilical venous serum samples were quantified by RIA using an automated chemiluminescent immunoassay system (Immulite, Diagnostic Products, Los Angeles, CA) as described previously for estradiol (17). The antibody for assay of cortisol was highly specific and exhibited minimal (<1%) cross-reactivity with cortisone, progesterone, 11-deoxycortisol, and 17-hydroxyprogesterone and 8.6% cross-reactivity with corticosterone. Levels of cortisol in maternal (n = 26) and umbilical (n = 26) venous plasma samples assayed undiluted were similar to respective values obtained when samples were diluted 1:2 and 1:3. The inter- and intraassay coefficients of variation were 10.5% and 6.3%, respectively. Maternal (n = 2) and umbilical venous (n = 6) serum samples from baboons in each of the treatment groups were also extracted with ethyl acetate and cortisol purified by Sephadex LH 20 (Pharmacia, Piscataway, NJ) column chromatography as described previously (2). Serum levels (nanomoles per liter) of cortisol in purified samples (624 ± 134) were comparable (correlation coefficient = 0.92) to respective values as determined before purification (681 ± 136) further confirming specificity of the chemiluminescent immunoassay for analysis of cortisol in the baboon. The concentration of cortisol in extracts of fetal lung was determined using a solid-phase ¹²⁵I RIA kit (Coat-A-Count, Diagnostic Products) the primary antibody of which is the same as that employed in the Immulite procedure. Briefly, 200–400 mg fetal lung was homogenized in 5 ml PBS and an aliquot removed for determination of protein using the bicinchoninic procedure (Sigma). Samples were then extracted twice with two volumes of ethyl acetate, solvent evaporated, extracts resuspended in 250 µl RIA buffer, and 25- and 50-µl aliquots analyzed. Cortisol levels in the 50-µl aliquots were uniformly 2-fold (overall mean ± SE, 2.05 ± 0.05) greater than in 25-µl aliquots and samples (n = 4) spiked with excess cortisol; the level of hormone detected (19 ± 2) was not different from that expected (16 ± 1). Fetal lung extracts from two animals in each of the treatment groups were also subjected to Sephadex LH 20 column chromatography. Cortisol levels (nanomoles per gram) in purified samples (0.15 ± 0.04) were comparable (correlation coefficient = 0.95) to respective values determined before purification (0.14 ± 0.03), further confirming specificity of the RIA for analysis of cortisol in fetal baboon lung. The umbilical serum concentrations of corticosteroid-binding globulin (CBG) were determined as described previously (21, 22).

Fetal lung glycogen

Lung glycogen was measured essentially as described by Carroll et al. (23). Briefly, pieces of fetal lung (250–900 mg) were sonicated in 5.0 ml distilled H₂0 (4 C, 45 sec), the homogenate mixed with 20 ml ethyl acetate, and the aqueous fraction mixed with 5.0 ml 10% trichloracetic acid (TCA), centrifuged (2000 x g, 10 min), and the supernatant decanted through 5% TCA-washed filter paper (#1, Whatman). The pellet was resuspended in 5.0 ml 5% TCA, filtered, and glycogen then precipitated overnight with 5.0 ml 95% ethanol and collected by centrifugation (2000 x g, 15 min). The glycogen pellet was dissolved in 2.0 ml distilled H₂0 and after addition of 10 ml of anthrone (0.5 mg anthrone and 10 mg thiourea/ml 72% H₂SO₄), samples including glycogen standards were heated at 100 C for 15 min, cooled, and absorbance measured at 620 nm.

	Results

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Maternal and umbilical venous estradiol levels were suppressed (P < 0.05) by approximately 95% by maternal administration of CGS 20267 (Table 1). Although treatment with CGS 20267 and estradiol benzoate restored (P < 0.05) maternal estradiol to normal, estrogen levels in umbilical serum were elevated (P < 0.05) to values only 30% of normal. In estrogen-suppressed baboons, serum levels of cortisol in both maternal and umbilical veins were lower (P < 0.05) than respective values in untreated baboons and samples from animals treated with CGS 20267 and estrogen. Levels of CBG in umbilical serum were similar in baboons untreated or treated with CGS 20267 or CGS 20267 and estrogen (Table 1).

View larger version (37K): [in this window] [in a new window]   Figure 1. Effects of aromatase inhibitor CGS 20267 on the developmental expression of SP-A protein in fetal lung of untreated baboons at mid- (d 100; n = 5) and late (d 165; n = 7 and 175; n = 8) gestation and on d 165 of gestation (term = 184 d) in baboons treated with CGS 20267 (1–2 mg/d sc; n = 12) or CGS 20267 plus estradiol (1–2 mg/d each sc; n = 7). Lung extracts were examined by immunoblot assay with enhanced chemiluminescence and results expressed as a percentage of values for a pooled sample of late gestation lungs from untreated baboons that was set at 100%. Values with different letter superscripts differ at P < 0.05 (ANOVA; Student Newman Keuls statistic).

View larger version (36K): [in this window] [in a new window]   Figure 2. Effects of CGS 20267 on the developmental expression of SP-B protein in fetal lung of untreated baboons at mid- (d 100; n = 5) and late (d 165; n = 7 and 175; n = 8) gestation and on d 165 of gestation in baboons treated with CGS 20267 (n = 12) or CGS 20267 plus estradiol (n = 7). See legend of Fig. 1 for methodological details. Values with different letter superscripts differ at P < 0.05 (ANOVA; Student Newman Keuls statistic).

Although peripheral serum cortisol levels were suppressed by approximately 35% in baboon fetuses of CGS 20267-treated mothers (Fig 3), cortisol levels in the fetal lung tissue of estrogen-suppressed baboons (0.12 ± 0.02 nmol/g) were similar to respective values in baboons untreated (0.14 ± 0.02) or treated with CGS 20267 and estrogen (0.13 ± 0.03).

View larger version (20K): [in this window] [in a new window]   Figure 3. Effect of CGS 20267 on cortisol concentrations in peripheral serum (Table 1) and extracts of lung of the baboon fetus on d 165–175 of gestation (n = 5/group). Values (mean ± SE) with different letter superscripts differ at P < 0.05 (ANOVA; Student Newman Keuls statistic).

View larger version (152K): [in this window] [in a new window]   Figure 4. Representative histology of sections of fetal lung obtained on d 100 (A) and 165 (B) of gestation from untreated baboons and on d 165 of gestation from baboons treated with CGS 20267 (C) or CGS 20267 plus estradiol benzoate (D) as described in legend to Table 1. Paraffin sections (4 µm) were rehydrated in graded alcohols and stained with hematoxylin and eosin. Original magnification, x100.

View larger version (106K): [in this window] [in a new window]   Figure 5. Representative photomicrographs of the immunocytochemical localization of 11ß-HSD-1 (A–D) and 11ß-HSD-2 (E–H) in the baboon fetal lung on d 100 (A, E) and d 165 of gestation (B–D and F–H) in animals that were untreated (A, B, E, F) or treated during the second half of gestation with CGS 20267 (C, G) or CGS 20267 plus estradiol benzoate (D, H) as described in the legend to Table 1. Sections were incubated with primary antibody to 11ß-HSD-1 or 11ß-HSD-2 and biotinylated antirabbit IgG. Original magnification, x400 (A, E) or x200.

	Discussion

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The results of the current study also demonstrated that cortisol levels in the fetal lung of estrogen-deprived baboons were similar to those in untreated baboons. The latter occurred despite a marked decline in total levels of fetal serum cortisol and presumably the unbound level of cortisol because concentrations of CBG were also similar in untreated and estrogen-deprived fetuses. Therefore, it is possible that the lung coordinated its production of cortisol by increasing uptake from the circulation and/or regulating local production. Previous studies have shown that conversion of 11-ketosteroids (e.g. cortisone) to 11-oxosteroids (e.g. cortisol) is increased in the rodent fetal lung in late gestation (24, 25) and human fetal lung in culture (26, 27). Moreover, surfactant phosphatidylcholine synthesis and 11ß-HSD-1 activity are highly correlated late in gestation in the fetal rat lung (28), and the latter may also occur in the baboon lung. Thus, expression of the 11ß-HSD-1 enzyme catalyzing conversion of biologically inactive cortisone to biologically active cortisol (6) in bronchiole epithelial cells and consequently potential for production of cortisol from cortisone were maintained at normal levels in estrogen-deprived baboons. The current study, however, also showed that bronchiolar epithelial cells of the baboon as in human fetal lung (29, 30) in late gestation expressed the 11ß-HSD-2 enzyme, which catalyzes the oxidation of cortisol to cortisone. Thus, the primate fetal lung also has the capacity to convert cortisol to inactive cortisone as originally shown by Murphy (31) in human fetal lung.

Interestingly, it appeared that 11ß-HSD-2 expression was decreased in fetal lungs of estrogen-suppressed baboons, although the latter must be confirmed using more quantitative approaches. However, a reduction in 11ß-HSD-2 expression is consistent with our previous studies using isotope dilution that the peripheral transfer constant for conversion of cortisol to cortisone by the baboon fetus was up-regulated by estradiol (32) and suppressed at term in baboon neonates delivered to mothers treated with an antiestrogen (33). Interestingly, estrogen had no effect on the overall conversion of cortisone to cortisol. Because the peripheral transfer constant represents the sum of all tissue beds metabolizing glucocorticoid, it remains to be determined whether cortisol-cortisone interconversion is regulated by estrogen in fetal baboon lung. Nevertheless, based on our immunocytochemical observations, the maintenance of high 11ß-HSD-1 and decreased 11ß-HSD-2 levels in fetal lung of estrogen-suppressed baboons could provide a mechanism to increase lung cortisol levels in the face of decreased availability of peripheral cortisol.

The results of the current study also suggest that both 11ß-HSD-1 and -2 were expressed in the same cells of the baboon fetal lung. These enzymes are also coexpressed in the baboon and human placental syncytiotrophoblast (1). In the placenta, estrogen has been shown to up-regulate both 11ß-HSD-1 and -2 expression (1, 2, 3), and 11ß-HSD-1 and -2 expression in the fetal lung was markedly increased between mid- and late gestation. However, in the current study, as in our previous experiments using isotope dilution, estrogen appeared to modulate only the oxidation of cortisol to cortisone, i.e. the 11ß-HSD-2 enzyme. Thus, 11ß-HSD-1 expression in fetal lung may be regulated by factors other than or in addition to estrogen. For example, cortisol has also been shown to modulate 11ß-HSD-1 expression in fetal and adult sheep liver (34). However, the role of cortisol on baboon fetal lung 11ß-HSD-1 expression remains to be ascertained.

The increase in SP-A and SP-B expression in fetal lung of untreated baboons of the current study confirms the elegant work of Coalson et al. (14). These investigators clearly showed using in situ hybridization that SP-A and SP-B were expressed in alveolar epithelial type II cells as well as bronchial and bronchiolar epithelial cells and that SP-C was expressed in loci of epithelial cells in respiratory bronchioles. Gao et al. (15) have also shown that SP-A mRNA levels in fetal baboon lung were barely detectable on d 92 of gestation increased 4-fold between d 120 and d 140 and an additional 7-fold by d 160. A similar pattern and developmental expression of SP-A and SP-B apparently occurs in the human fetal lung (35, 36). Finally, although surfactant synthesis is normal in SP-A-deficient mice (37, 38), SP-A null mice exhibit increased susceptibility to infection (39). Therefore, it appears that SP-A may primarily exhibit an important nonsurfactant associated role (e.g. host defense) in lung function (40).

The regulation of SP-A and SP-B gene expression appears to be extremely complex and multifactorial in nature (15, 41, 42). In studies of human fetal lung in culture, Boggaram et al. (41, 42, 43) have shown that cAMP and glucocorticoids increase transcriptional activity of the SP-A gene but that paradoxically glucocorticoids also cause a dose-dependent inhibition of SP-A mRNA stability. Similar to observations in midgestation human fetal lungs, cAMP-enhanced SP-A gene expression in baboon fetal lungs obtained on d 90 and d 140 of gestation and cAMP-induced SP-A expression was inhibited by dexamethasone in a dose-dependent manner (16). However, these effects were not manifest in lungs obtained from baboons on d 165–174 of gestation, indicating that there is a decrease in the responsiveness of the baboon fetal lung to the stimulatory effects of cAMP and the inhibitory effects of glucocorticoids. Further study is required to ascertain the factors acting/interacting to regulate basal expression of the surfactant proteins as well as lung growth and differentiation. However, the similarity in gene expression and developmental regulation in the baboon and human support the use of this nonhuman primate model to perform such studies.

	Acknowledgments

 
The generous gift of CGS 20267 was graciously provided by Norvartis Pharma AG (Basel Switzerland). We sincerely appreciate the secretarial assistance of Sandra Huband with the manuscript; Nicholas Zachos with the preparation of the photomicrographs and lung cortisol assays; Geoffrey Hammond, Ph.D. (London Regional Cancer Centre, London, Ontario, Canada), for CBG analyses; Marcia G. Burch with the immunocytochemistry; and Carol Stapanowich, Ph.D., with the histology. The enthusiasm and early work of Steven G. Bassett, Ph.D., on baboon lung development is sincerely appreciated.

	Footnotes

 
This work was supported by NIH Research Grant R01 HD-13294 and HL-19737.

Abbreviations: 11ß-HSD, 11ß-Hydroxysteroid dehydrogenase; CBG, corticosteroid-binding globulin; SP, surfactant protein; TCA, trichloroacetic acid.

Received February 12, 2002.

Accepted October 14, 2002.

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