help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0556
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/7/4309    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rajatapiti, P.
Right arrow Articles by Tibboel, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rajatapiti, P.
Right arrow Articles by Tibboel, D.
Related Collections
Right arrow Adrenal and Hypertension
Right arrow Pediatric Endocrinology
Right arrow Thyroid
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4309-4314
Copyright © 2005 by The Endocrine Society

Expression of Glucocorticoid, Retinoid, and Thyroid Hormone Receptors during Human Lung Development

Prapapan Rajatapiti, Monique H. A. Kester, Ronald R. de Krijger, Robbert Rottier, Theo J. Visser and Dick Tibboel

Department of Pediatric Surgery (P.R., R.R., D.T.), Erasmus MC-Sophia Children’s Hospital-University Medical Center, 3015 GJ Rotterdam, The Netherlands; Department of Internal Medicine (P.R., M.H.A.K., T.J.V.), Department of Pathology (R.R.d.K.), Josephine Nefkens Institute, and Department of Cell Biology and Genetics (R.R.), Erasmus MC-University Medical Center, 3015 GJ Rotterdam, The Netherlands; and Department of Surgery (P.R.), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand

Address all correspondence and requests for reprints to: Dick Tibboel, M.D., Ph.D., Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, University Medical Center, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: j.illsley{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Context: Although glucocorticoid hormone, thyroid hormone, and retinoic acid play important roles in fetal development, the expression of their receptors in human lung is still unknown.

Objective: The aim of this study was to investigate the ontogeny of glucocorticoid receptor (GR){alpha}, thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and retinoid X receptors (RXRs) mRNA expression in human lungs.

Design: Lungs from human fetuses and neonates (13.5–41 wk gestation; n = 20) as well as adults (n = 5) were analyzed by real-time PCR to monitor the ontogeny of mRNA expression for each receptor. In addition, immunohistochemistry was performed to show the cellular distribution of the different receptors.

Results: The expression of GR{alpha}, TRs, RARs, and RXRs was already detected in the earliest developmental stages analyzed. There was no significant difference in mRNA expression between developmental groups for any of the genes studied. However, for fetal and neonatal samples, there were positive correlations between gestational age and mRNA expression for RAR{alpha} (r = 0.665; P = 0.001), RXR{alpha} (r = 0.444; P = 0.050), and RXR{gamma} (r = 0.464; P = 0.039). Immunohistochemical studies showed the presence of GR{alpha}, TRs, RARs, and RXRs in the nuclei of both epithelial and mesenchymal cells, albeit more pronounced in epithelium of larger airways.

Conclusions: The detection of GR{alpha}, TRs, RARs, and RXRs expression in human lung as early as 13.5 wk gestation implies an early potential for therapeutic or toxic effects by exogenous analogs or by excess of endogenous ligands.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN HUMANS, LUNG development starts around the fourth week of gestation with the formation of two endodermally derived lung buds. The main bronchi and segmental bronchi are formed through branching morphogenesis, until the bronchial tree is completed by wk 16. The lumina of the bronchi and terminal bronchioles become larger, and vascularization is more prominent during the canalicular period (17–26 wk gestation). Further subdivision of bronchioles and formation of primitive alveoli occurs in the saccular period (24–36 wk gestation until term). In the alveolar period (from 36 wk onward), the gas exchange surface of the lung increases due to the thinning of the squamous epithelial layer, forming thin-walled alveoli. This alveolization continues after birth and is completed in childhood (1, 2, 3, 4, 5).

Many factors, including hormonal, biochemical, and physical factors, have been identified that modulate growth and development of the lungs (4, 6, 7, 8). Among these, glucocorticoids, thyroid hormone, and retinoic acid (RA) are described to influence the growth of lungs. Glucocorticoid plays a role in the regulation of surfactant proteins and lipids during lung maturation (1, 7); therefore, antenatal corticosteroids were recommended by National Institutes of Health consensus to all fetuses between 24 and 34 wk gestation at risk of preterm delivery (6, 9). This will lead to an induction of surfactant production, an acceleration of lung maturation, and an increase in lung compliance. Thyroid hormone, independently or in conjunction with glucocorticoids, has been implicated in the growth and maturation of the perinatal lung. Early reports suggested that thyroid hormone concentrations in cord blood of premature infants with respiratory distress syndrome were low, relative to age and birth weight-matched controls, but these findings were not supported in later studies (10). Vitamin A, and its active metabolite RA, has a role in cellular differentiation via binding to its receptors (5, 11, 12). In animal studies, both the lack and excess of vitamin A during embryonic development result in congenital malformations such as infertility, anopthalmia, and lung hypoplasia (11, 13, 14). In humans, lower plasma vitamin A levels were found in prematurely born infants, especially in cases with respiratory distress or pulmonary hypoplasia associated with congenital diaphragmatic hernia (15, 16).

The actions of these ligands are mediated through the activation of their receptors, which belong to a superfamily of ligand-dependent transcriptional proteins. All members of the family share a highly conserved similar modular structure with discrete functional domains for hormone binding, DNA binding, and transactivation. Through the DNA binding domain, the receptor binds to specific DNA sequences as monomers, homodimers, or heterodimers (17, 18). Unlike other steroid hormone receptors, glucocorticoid receptor (GR){alpha} resides primarily in the cytoplasm of cells in the absence of ligands (19). Thyroid hormone receptors (TRs) are encoded by two genes ({alpha} and ß), each producing several isoforms, among which TR{alpha}1 and TRßs act as functional receptors. Retinoid receptors are classified into two subtypes, RA receptors (RARs) and retinoid X receptors (RXRs). Each subtype comprises three major isoforms, {alpha}, ß, and {gamma}. Although 9-cis-RA binds to both RARs and RXRs, all-trans-RA binds preferably to RARs (20). Aside from the classical model in which the steroid hormones elicit a transcriptional response upon binding to their cognate receptor, there appears to be a nongenomic action described for at least the glucocorticoids and the thyroid hormone. This nongenomic response occurs rapidly (within minutes) and is unaffected by inhibitors of transcription and protein synthesis. The site of the response can be at the plasma membrane, in the cytoplasm, and in cellular organelles (21, 22, 23, 24).

Because the level of nuclear receptor expression determines cell sensitivities to certain hormones (25), the presence of these receptors in human lung has been studied previously by various techniques (26, 27, 28, 29). However, the ontogeny of their expression has not been shown in a systematic way before. To elucidate their expression patterns during human lung development, we examined the expression of GR{alpha}, TR{alpha}, TRß, RARs, and RXRs in human lung tissue, from 13.5 wk gestation until term, by real-time PCR and immunohistochemistry.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue samples

After approval of the University Ethical Committee of the experimental design and protocols, lung tissues were retrieved from the archives of the Department of Pathology, Erasmus MC, Rotterdam. Fetal and neonatal lung tissues (n = 20) were obtained from either elective termination of pregnancy or autopsies. All samples were harvested within 24 h after death. All neonatal cases died of reasons other than pulmonary abnormalities with known postconceptional age and in the absence of documented growth retardation. No gross anatomical abnormalities were documented in any of these cases on standardized pediatric pathology evaluations. The lung samples were randomly selected from either side. There were five samples for each morphological distinct developmental stage: pseudoglandular stage (13.5–17 wk gestation; mean, 16 wk), canalicular stage (18–26 wk gestation; mean, 21.8 wk), saccular stage (29–36 wk gestation; mean, 30.4 wk), and alveolar stage (37–41 wk of gestation; mean, 39 wk). Another five lung tissues from adult surgical resection specimens (normal lung tissue resected along with a tumor) were included (25–49 yr; mean, 38 yr). There were no pulmonary abnormalities in any of the lung specimens, especially no sign of pulmonary hypoplasia on histological screening. Tissue samples were snap-frozen and stored at –80 C before RNA analysis. For immunohistochemical studies, tissues were fixed by immersion in 4% buffered formalin and embedded in paraffin. Subsequently, 5-µm-thick sections were mounted on 3-amino-propyl-trioxysilane-coated glass slides (Sigma, St. Louis, MO) and processed for immunohistochemistry.

RNA extraction and cDNA synthesis

Total RNA was extracted from frozen lung tissues using TRIzol reagent (Invitrogen, Breda, The Netherlands), according to the manufacturer’s instruction. Total RNA was quantified by measuring the absorbance at 260 nm, and the purity was checked with 260/280 nm absorbance ratio. cDNA synthesis was carried out in a reaction vol of 20 µl containing 500 ng total RNA, 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM MgCl2, 10 mM dithiothreitol, 100 ng random hexamer primer, 500 µM of each deoxynucleotide triphosphate (dATP, dGTP, dCTP, and dTTP), 10 U ribonuclease inhibitor, and 200 U Moloney murine leukemia virus reverse transcriptase (all reagents were obtained from Invitrogen). The samples were incubated for 60 min at 37 C, followed by incubation for 15 min at 99 C. Negative control samples were prepared by omission of the Moloney murine leukemia virus reverse transcriptase.

Real-time quantitative PCR

Real-time PCR was performed using an iCycler IQ Real time PCR detection system (Bio-Rad Laboratories, Inc., Veenendaal, The Netherlands) and qPCR Core kit for SYBR Green I (Eurogentec, Seraing, Belgium). Gene-specific primers used in this study (Table 1Go) were designed using the sequences accessible in the NCBI Reference Sequence (www.ncbi.nlm.nih.gov/RefSeq) and Primer3 software (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi). A total reaction vol of 25 µl contained 1x reaction buffer, 3.5 mM MgCl2, 200 µM of each deoxynucleotide triphosphate, 250 nM of each primer, and 1 µl cDNA. The PCR thermal cycle conditions were: 10 min of initial denaturation at 95 C, followed by 40 cycles of 30 sec at 95 C, 30 sec at 58 C for annealing, 30 sec at 60 C, and 15 sec at 75 C. To verify the specificity of the amplified products, each PCR was followed by a melting curve analysis from 55–95 C. Each sample was run as a triplicate, and mRNA of each target gene was determined simultaneously in a 96-well plate. Negative control samples and reactions mixed without cDNA templates were run in parallel.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Primer sequences for real-time PCR

 
PCR results are shown as the relative expression level of normalized samples [{Delta} cycle threshold (Ct)] in relation to the expression of the "calibrator" sample of 13.5 wk gestation (2–{Delta} {Delta} Ct), which was arbitrarily set at 100% (arbitrary value = 1). The Ct value refers to the cycle number at which the PCR plot crosses the threshold line, {Delta} Ct is calculated by subtracting Ct value of the corresponding glyceraldehyde-3-phosphate dehydrogenase control (endogenous reference control) from the specific Ct value of the target, and {Delta} {Delta} Ct is obtained by subtracting the {Delta} Ct of each experimental sample by the {Delta} Ct of the calibrator sample (30).

Statistical analysis

Data from the real-time RT-PCR are shown as mean 2–{Delta} {Delta} Ct± SEM or individually. The differences in mRNA expression between groups were analyzed with one-way ANOVA with post hoc least-significant difference test. The correlations between mRNA expression and gestational age were determined by nonparametric Spearman’s correlation. P ≤ 0.05 was considered statistically significant (see Fig. 2Go, which includes correlation coefficients only for groups for which P ≤ 0.05). All statistics were calculated using a SPSS statistical package (version 11.0; SPSS, Inc., Chicago, IL).



View larger version (26K):
[in this window]
[in a new window]
  		FIG. 2. Relation between GR{alpha}, TR{alpha} 1, TRß, RARs, and RXRs mRNA expression and gestational age of 20 samples from 13.5–41 wk gestation. The r-values show Spearman’s correlation coefficient with gestational age.

 
Immunohistochemistry

Immunohistochemistry was performed using a ChemMate Dako EnVision Detection Kit, Peroxidase/DAB, Rabbit/Mouse (K5007, DakoCytomation B.V., Heverlee, The Netherlands). In brief, after deparaffinization for 10 min in xylene and rinsing in 100% alcohol twice, slides were treated with 3% H2O2 in methanol for 20 min to block the endogenous peroxidase activity. For antigen retrieval, the slides were subjected to a 15-min microwave treatment in Tris/EDTA buffer (pH 9.0) or citric acid buffer (pH 6.0). Sections were incubated for 30 min at room temperature with primary antibody (Table 2Go) in a humidified chamber. After rinsing twice with PBS/0.1% Tween 20, slides were incubated for 30 min at room temperature with HRP-conjugated dextran polymer reagent. Sections were then rinsed twice with PBS before peroxidase was detected by incubation with 3,3'-diaminobenzidine tetrahydrochloride (1:50 dilution of ChemMate DAB+ Chromogen in ChemMate Substrate Buffer). Finally, slides were rinsed with running tap water and counterstained with hematoxylin, dehydrated through graded alcohol and xylene, and mounted. Negative controls were performed by omission of the primary antibodies.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Primary antibodies for immunohistochemistry

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
mRNA expressions

The expressions of the mRNA for GR{alpha}, TR{alpha}1, TRß, RARs, and RXRs were detected in all the samples examined. Figure 1Go shows average mRNA expression (mean ± SEM) of the different morphological stages. The mRNA expression of all genes studied was low in the pseudoglandular group and increased during the canalicular and the saccular stages. For RAR{alpha} and RAR{gamma}, mRNA expression increased with age until adult, whereas the expression of GR{alpha}, TR{alpha}1, RARß, and all RXRs was highest in the saccular or the alveolar group. Although there was no significant difference in mRNA expression between developmental groups for all genes studied, there were discernable differences in mRNA expression during development. When individual data points from fetus and newborn samples (13.5–41 wk gestation) were plotted against gestational age (Fig. 2Go), there were significant positive correlations between age and mRNA expression of RAR{alpha} (r = 0.665; P = 0.001), RXR{alpha} (r = 0.444; P = 0.050), and RXR{gamma} (r = 0.464; P = 0.039). Melting curve analysis showed the generation of specific products in all PCRs, as was confirmed by running several samples on agarose gel (data not shown).



View larger version (29K):
[in this window]
[in a new window]
  		FIG. 1. The ontogenic change of mRNA expression of GR{alpha}, TR{alpha} 1, TRß, RARs, and RXRs in human lungs. Samples were grouped according to their morphological stages and gestational age: pseudoglandular (13.5–17 wk), canalicular (18–26 wk), saccular (29–36 wk), alveolar (37–41 wk), and adult (25–49 yr); n = five per group. Data are shown as mean 2–{Delta} {Delta} Ct± SEM (as outlined in Materials and Methods). There was no significant difference in mRNA expression in all encoded genes (P > 0.05).

 
Immunohistochemistry

Immunoreactivity of GR{alpha}, TR{alpha}, TRß, RARs, and RXRs was detected in the nuclei of cells in all samples. GR{alpha} reactivity was detected mainly in epithelial cells (Fig. 3AGo). TR{alpha} was expressed in both epithelial and mesenchymal cells (Fig. 3BGo), whereas TRß reactivity was detected in the epithelial cells and endothelial cells of arteries (Fig. 3CGo). Immunoreactivities of RARs and RXRs were detected in virtually all epithelial cells and in some mesenchymal cells (Fig. 3Go, D–I). The expression pattern of each receptor was similar in all developmental groups. Because the immunohistochemistry was basically to demonstrate the regions and cellular distribution of the receptors, we did not attempt to quantify the staining intensity.



View larger version (163K):
[in this window]
[in a new window]
  		FIG. 3. Immunostaining of representative samples of human fetal lung. All pictures were taken from samples of 18 wk gestation except for TRß (32 wk) and RXRß (13.5 wk). The immunoreactivity was visualized by diaminobenzidine, positive cells giving a brown color at the site of reaction. A, GR immunoreactivity was expressed mainly in nuclei of epithelial cells. B, TR{alpha} was detected in both epithelial and mesenchymal cells, whereas TRß (C) was detected in airway epithelium and some vascular endothelial cells (arrow). Immunoreactivities of RAR{alpha} (D), RARß (E), RAR{gamma} (F), RXR{alpha} (G), RXRß (H), and RXR{gamma} (I) were detected virtually in all epithelial and in some mesenchymal cells (scale bar, 50 µm).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The developing lung undergoes a series of complex changes both during embryogenesis and after birth. Although a number of studies were conducted to evaluate the roles of glucocorticoids, thyroid hormone, and RA in lung formation, there is limited knowledge on the ontogeny of the expression of their receptors during human lung development. In this study, we investigated the mRNA expression of GR{alpha}, TRs, RARs, and RXRs in human lung throughout gestation, using real-time quantitative PCR and immunohistochemistry. We detected mRNA and protein expression of all receptors in human lung from the earliest stage, 13.5 wk gestation, onward.

The GR is a ubiquitously expressed hormone-dependent transcription factor involved in the regulation of many physiological processes. In humans, Ballard and Ballard (26) first reported GR mRNA expression in lungs of fetuses and neonates (age ranging from 12–43 wk gestation) using cytoplasmic binding and nuclear uptake assays. In 1990, Labbe et al. (27) measured GR concentration in fetuses (15–28 wk gestation), infants, and children (2 months to 9 yr). The receptor concentration in the fetuses was high, irrespective of gestational age, and the mean concentration was significantly lower postnatally. Moreover, to evaluate the functional role of GR, several experiments with mutant mice have revealed that lung maturation was delayed in mice with low or no GR expression (3, 31). The lungs of the GR null mice are condensed and hypercellular, with reduced septal thinning, leading to an increase in the airway-to-capillary diffusion distance.

Our quantitative PCR data showed a slightly different pattern, i.e. low GR{alpha} mRNA expression at the pseudoglandular stage, increasing during gestation, and lower in adults. We did not include infant specimens in our study. We found the immunohistochemical localization of the GR in the nuclei of airway epithelium and mesenchymal cells, albeit more prominent in the epithelium. This finding is consistent with previous studies performed in adult lungs, which showed GR to be localized in alveolar wall, airway epithelium, and vascular endothelial cells (32, 33). Oakley et al. (19) showed that the GRß resides in the nucleus of cells, irrespective of hormonal binding, whereas GR{alpha} is in the cytoplasm and translocates to the nucleus upon ligand binding.

Thyroid hormone is essential for normal growth and development. Serum T3 and T4 are present in the fetal circulation before the onset of fetal thyroid hormone production, albeit at low levels (34, 35). During the first trimester, maternal thyroid hormone is transferred into fetal circulation via the secondary yolk sac; and during the second trimester, it is transferred directly into fetal blood. Subsequently, there is an increasing contribution of thyroid hormone production by the fetal thyroid gland (35). The role of thyroid hormone in lung development is exerted predominantly in the late phase of lung development, with regard to the regulation of surfactant production. In rats, administration of T3 accelerates the process of septation, resulting in a greater alveolar surface area (36). TR{alpha}1 and TRß act as T3-dependent transcription factors. TRs can bind to the DNA as homodimers or as heterodimers with other nuclear receptors, such as RXRs (18). Increases in TR binding capacity and occupancy by T3 during lung development in rabbits suggest a physiological role of thyroid hormone in lung development (6). Little is known about the cellular pattern of TR in the developing human lung. In this study, we demonstrated that TR{alpha}1 mRNA expression increases from pseudoglandular to alveolar stage and then declines in adult specimens. Both TR{alpha} and TRß proteins were expressed in nuclei of epithelial cells. TRß was also present in endothelial cells of the arteries. The expression of TR{alpha} in mesenchymal cells combined with the expression of TRß in endothelial cells is of interest in light of the observation that changes in the T3 and T4 levels have an effect on the heart and vascular system (37). Endothelium-dependent dilation of conductance vessels is impaired in hypothyroidism but augmented in hyperthyroidism. However, dilation of resistance vessels in skeletal muscle appears unchanged in both hypo- and hyperthyroidism (38). Treatment of rats with T3 increased the endothelium-dependent relaxation of the renal artery, probably by increasing the vascular cAMP content (39). Particularly, the exposure to T3 for 8 wk led to an enhanced expression of endothelial nitric oxide synthase and thus the release of NO, which appeared to be the predominant endothelium-derived vasodilator. In another study, Heron et al. (40) showed that 12 d of exposure to T3 in neonates resulted in a considerable proliferation of coronary capillaries, which declined after 28 d of treatment. The expression of the two receptors in the endothelium and surrounding tissue during gestation may contribute to the expansion of the pulmonary vasculature, which is already present early in development (41).

RA is an oxidative metabolite of vitamin A and is involved in the control of many biological processes. The regulation of the differentiation processes by RA involves the ability of these signaling molecules to alter the expression of a wide variety of genes. For example, RA regulates the expression of hox genes during embryonic branching morphogenesis to favor growth of proximal airways and to suppress distal epithelial bud formation (42, 43).

RARs serve distinct functions in lung development. RXRs can act as homodimers or heterodimers with a variety of nuclear receptors, including RARs and TRs (43, 44). RAR{alpha} mediates alveolar growth during the perinatal period of alveolarization (45). RARß inhibits septation (46), whereas RAR{gamma} is needed for normal lung elastin production and alveolarization (47). Administration of all-trans RA to normal neonatal rats enhances alveolar septal formation without increasing alveolar surface area (11). RAR{alpha}/RXR{alpha} and RAR{alpha}/ß double-knockout mice were shown to have lung hypoplasia or agenesis, demonstrating the importance of these receptors during the early phases of lung development (13, 14, 48).

Previously, a study from Kimura et al. (28) has shown that the mRNA levels of RXR{gamma} at proximal (trachea and main bronchus) and distal sites, of RARß at distal sites, and of RAR{gamma} at proximal sites were significantly higher in human fetal lung (13–16 wk gestation) compared with adults. In this study, we found no significant difference in mRNA expression between different developmental stages for the RARs and RXRs studied. However, we found positive correlations between gestation age and expression of RAR{alpha}, RXR{alpha}, and RXR{gamma} from 13.5–41 wk.

In conclusion, mRNA expression of GR{alpha}, TRs, RARs, and RXRs were detected in human lung from 13.5 wk gestation onward. These results indicate that, as far as receptors are concerned, human fetal lung has the potential to respond to glucocorticoids, thyroid hormone, and RA as early as 13.5 wk gestation and potentially earlier, which implies an early potential for therapeutic benefits by exogenous analogs. However, more investigation is needed because there is a possibility of toxic effects by excess of endogenous ligands as well. We consider the results from this study as baseline data for further comparative studies involving abnormal lung development, such as in cases of pulmonary hypoplasia with or without diaphragmatic hernia.


   Acknowledgments
 
The authors thank Jessica de Rooij from Department of Pathology, Josephine Nefkens Institute, Erasmus MC, for her generous help with the sample preparations; and Frank van der Panne for art work.


   Footnotes
 
P.R. was supported by Faculty of Medicine, Chulalongkorn University; Ministry of Education, Royal Thai Government; and the Sophia Foundation for Medical Research (Sophia Foundation for Medical Research project no. 412).

First Published Online April 19, 2005

Abbreviations: Ct, Cycle threshold; GR, glucocorticoid receptor; RA, retinoic acid; RAR, RA receptor; RXR, retinoid X receptor; TR, thyroid hormone receptor.

Received March 11, 2005.

Accepted April 13, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Bolt RJ, van Weissenbruch MM, Lafeber HN, Delemarre-van de Waal HA 2001 Glucocorticoids and lung development in the fetus and preterm infant. Pediatr Pulmonol 32:76–91[CrossRef][Medline]
  2. Zoetis T, Hurtt ME 2003 Species comparison of lung development. Birth Defects Res B Dev Reprod Toxicol 68:121–124[Medline]
  3. Chinoy MR 2003 Lung growth and development. Front Biosci 8:392–415
  4. Copland I, Post M 2004 Lung development and fetal lung growth. Paediatr Respir Rev 5(Suppl A):S259–S264
  5. Maden M 2004 Retinoids in lung development and regeneration. Curr Top Dev Biol 61:153–189[Medline]
  6. Merrill JD, Ballard RA 1998 Antenatal hormone therapy for fetal lung maturation. Clin Perinatol 25:983–997[Medline]
  7. Keijzer R, van Tuyl M, Tibboel D 2000 Hormonal modulation of fetal pulmonary development: relevance for the fetus with diaphragmatic hernia. Eur J Obstet Gynecol Reprod Biol 92:127–133[CrossRef][Medline]
  8. Cardoso WV, Williams MC 2001 Basic mechanisms of lung development: Eighth Woods Hole Conference on Lung Cell Biology 2000. Am J Respir Cell Mol Biol 25:137–140[Free Full Text]
  9. Lyons CA, Garite TJ 2002 Corticosteroids and fetal pulmonary maturity. Clin Obstet Gynecol 45:35–41[CrossRef][Medline]
  10. Job L, Emery JR, Hopper AO, Deming DD, Nystrom GA, Clark SJ, Nelson JC 1997 Serum free thyroxine concentration is not reduced in premature infants with respiratory distress syndrome. J Pediatr 131:489–492[Medline]
  11. Maden M 2000 The role of retinoic acid in embryonic and post-embryonic development. Proc Nutr Soc 59:65–73[Medline]
  12. Massaro D, Massaro GD 2003 Retinoids, alveolus formation, and alveolar deficiency: clinical implications. Am J Respir Cell Mol Biol 28:271–274[Free Full Text]
  13. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, Mark M 1994 Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120:2749–2771[Abstract]
  14. Lohnes D, Mark M, Mendelsohn C, Dolle P, Decimo D, LeMeur M, Dierich A, Gorry P, Chambon P 1995 Developmental roles of the retinoic acid receptors. J Steroid Biochem Mol Biol 53:475–486[CrossRef][Medline]
  15. Major D, Cadenas M, Fournier L, Leclerc S, Lefebvre M, Cloutier R 1998 Retinol status of newborn infants with congenital diaphragmatic hernia. Pediatr Surg Int 13:547–549[CrossRef][Medline]
  16. Biesalski HK, Nohr D 2003 Importance of vitamin-A for lung function and development. Mol Aspects Med 24:431–440[CrossRef][Medline]
  17. Whitfield GK, Jurutka PW, Haussler CA, Haussler MR 1999 Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function. J Cell Biochem 75(Suppl 32):110–122
  18. Aranda A, Pascual A 2001 Nuclear hormone receptors and gene expression. Physiol Rev 81:1269–1304[Abstract/Free Full Text]
  19. Oakley RH, Webster JC, Jewell CM, Sar M, Cidlowski JA 1999 Immunocytochemical analysis of the glucocorticoid receptor {alpha} isoform (GR{alpha}) using GR{alpha}-specific antibody. Steroids 64:742–751[CrossRef][Medline]
  20. Chambon P 1996 A decade of molecular biology of retinoic acid receptors. FASEB J 10:940–954[Abstract]
  21. Makara GB, Haller J 2001 Non-genomic effects of glucocorticoids in the neural system. Evidence, mechanisms and implications. Prog Neurobiol 65:367–390[CrossRef][Medline]
  22. Simoncini T, Genazzani AR 2003 Non-genomic actions of sex steroid hormones. Eur J Endocrinol 148:281–292[Abstract]
  23. Wehling M 1997 Specific, nongenomic actions of steroid hormones. Annu Rev Physiol 59:365–393[CrossRef][Medline]
  24. Bassett JH, Harvey CB, Williams GR 2003 Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol 213:1–11[CrossRef][Medline]
  25. Smirnov AN 2002 Nuclear receptors: nomenclature, ligands, mechanisms of their effects on gene expression. Biochemistry (Mosc) 67:957–977[CrossRef][Medline]
  26. Ballard PL, Ballard RA 1974 Cytoplasmic receptor for glucocorticoids in lung of the human fetus and neonate. J Clin Invest 53:477–486
  27. Labbe A, Grizard G, Dechelotte P, Raynaud EJ 1990 Glucocorticoid receptor concentrations in human lung at different growth stages. Pediatr Pulmonol 9:140–145[Medline]
  28. Kimura Y, Suzuki T, Kaneko C, Darnel AD, Moriya T, Suzuki S, Handa M, Ebina M, Nukiwa T, Sasano H 2002 Retinoid receptors in the developing human lung. Clin Sci (Lond) 103:613–621[Medline]
  29. Pujols L, Mullol J, Torrego A, Picado C 2004 Glucocorticoid receptors in human airways. Allergy 59:1042–1052[CrossRef][Medline]
  30. Livak KJ, Schmittgen TD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-{Delta} {Delta} C(T)) method. Methods 25:402–408[CrossRef][Medline]
  31. Cole TJ, Solomon NM, Van Driel R, Monk JA, Bird D, Richardson SJ, Dilley RJ, Hooper SB 2004 Altered epithelial cell proportions in the fetal lung of glucocorticoid receptor null mice. Am J Respir Cell Mol Biol 30:613–619[Abstract/Free Full Text]
  32. Adcock IM, Gilbey T, Gelder CM, Chung KF, Barnes PJ 1996 Glucocorticoid receptor localization in normal and asthmatic lung. Am J Respir Crit Care Med 154:771–782[Abstract]
  33. Pujols L, Xaubet A, Ramirez J, Mullol J, Roca-Ferrer J, Torrego A, Cidlowski JA, Picado C 2004 Expression of glucocorticoid receptors {alpha} and ß in steroid sensitive and steroid insensitive interstitial lung diseases. Thorax 59:687–693[Abstract/Free Full Text]
  34. Burrow GN, Fisher DA, Larsen PR 1994 Maternal and fetal thyroid function. N Engl J Med 331:1072–1078[Free Full Text]
  35. Calvo RM, Jauniaux E, Gulbis B, Asuncion M, Gervy C, Contempre B, Morreale de Escobar G 2002 Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab 87:1768–1777[Abstract/Free Full Text]
  36. Massaro D, Teich N, Massaro GD 1986 Postnatal development of pulmonary alveoli: modulation in rats by thyroid hormones. Am J Physiol 250:R51–R55
  37. Klein I, Ojamaa K 2001 Thyroid hormone and the cardiovascular system. N Engl J Med 344:501–509[Free Full Text]
  38. McAllister RM, Albarracin I, Jasperse JL, Price EM 2005 Thyroid status and endothelium-dependent vasodilation in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 288:R284–R291
  39. Bussemaker E, Popp R, Fisslthaler B, Larson CM, Fleming I, Busse R, Brandes RP 2003 Hyperthyroidism enhances endothelium-dependent relaxation in the rat renal artery. Cardiovasc Res 59:181–188[CrossRef][Medline]
  40. Heron MI, Kolar F, Papousek F, Rakusan K 1997 Early and late effect of neonatal hypo- and hyperthyroidism on coronary capillary geometry and long-term heart function in rat. Cardiovasc Res 33:230–240[Abstract/Free Full Text]
  41. Parera MC, van Dooren M, van Kempen M, de Krijger R, Grosveld F, Tibboel D, Rottier R 2005 Distal angiogenesis: a new concept for lung vascular morphogenesis. Am J Physiol Lung Cell Mol Physiol 288:L141–L149
  42. Cardoso WV, Mitsialis SA, Brody JS, Williams MC 1996 Retinoic acid alters the expression of pattern-related genes in the developing rat lung. Dev Dyn 207:47–59[CrossRef][Medline]
  43. Ross SA, McCaffery PJ, Drager UC, De Luca LM 2000 Retinoids in embryonal development. Physiol Rev 80:1021–1054[Abstract/Free Full Text]
  44. Rowe A 1997 Retinoid X receptors. Int J Biochem Cell Biol 29:275–278[CrossRef][Medline]
  45. Massaro GD, Massaro D, Chambon P 2003 Retinoic acid receptor-{alpha} regulates pulmonary alveolus formation in mice after, but not during, perinatal period. Am J Physiol Lung Cell Mol Physiol 284:L431–L433
  46. Massaro GD, Massaro D, Chan WY, Clerch LB, Ghyselinck N, Chambon P, Chandraratna RA 2000 Retinoic acid receptor-ß: an endogenous inhibitor of the perinatal formation of pulmonary alveoli. Physiol Genomics 4:51–57[Abstract/Free Full Text]
  47. McGowan S, Jackson SK, Jenkins-Moore M, Dai H-H, Chambon P, Snyder JM 2000 Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol 23:162–167[Abstract/Free Full Text]
  48. Mollard R, Viville S, Ward SJ, Decimo D, Chambon P, Dolle P 2000 Tissue-specific expression of retinoic acid receptor isoform transcripts in the mouse embryo. Mech Dev 94:223–232[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
Y. Maeda, V. Dave, and J. A. Whitsett
Transcriptional Control of Lung Morphogenesis
Physiol Rev, January 1, 2007; 87(1): 219 - 244.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. P. Saelzler, C. C. Spackman, Y. Liu, L. C. Martinez, J. P. Harris, and M. K. Abe
ERK8 Down-regulates Transactivation of the Glucocorticoid Receptor through Hic-5
J. Biol. Chem., June 16, 2006; 281(24): 16821 - 16832.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
M G Gnanalingham, A Mostyn, D S Gardner, T Stephenson, and M E Symonds
Developmental regulation of the lung in preparation for life after birth: hormonal and nutritional manipulation of local glucocorticoid action and uncoupling protein-2.
J. Endocrinol., March 1, 2006; 188(3): 375 - 386.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/7/4309    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rajatapiti, P.
Right arrow Articles by Tibboel, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rajatapiti, P.
Right arrow Articles by Tibboel, D.
Related Collections
Right arrow Adrenal and Hypertension
Right arrow Pediatric Endocrinology
Right arrow Thyroid

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals