Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039
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ABSTRACT |
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Retinoids are known to play important roles in
organ development of the lung. Retinoids exert their activity by
modulating the expression of numerous genes, generally influencing gene
transcription, in target cells. In the present work, the mechanism by
which retinoic acid (RA) regulates surfactant protein (SP) B expression
was assessed in vitro. RA (9-cis-RA)
enhanced SP-B mRNA in pulmonary adenocarcinoma cells (H441 cells) and
increased transcriptional activity of the SP-B promoter in both H441
and mouse lung epithelial cells (MLE-15). Cotransfection of H441 cells
with retinoid nuclear receptor (RAR)-, -
, and -
and retinoid X receptor (RXR)-
further increased the response of the
SP-B promoter to RA. Treatment of H441 cells with RA increased
immunostaining for the SP-B proprotein and increased the
number of cells in which the SP-B proprotein was detected. An RA
responsive element mediating RA stimulation of the human SP-B promoter
was identified. RAR-
and -
and RXR-
but not RAR-
or RXR-
and -
were detected by immunohistochemical analysis of H441 cells.
RA, by activating RAR activity, stimulated the transcription and
synthesis of SP-B in pulmonary adenocarcinoma cells.
surfactant protein B; glucocorticoid receptor; thyroid transcription factor-1
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INTRODUCTION |
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RETINOIC ACID (RA), a derivative of vitamin A, plays
highly diverse roles in cell proliferation, differentiation, and organ development. RA exerts its biological activity by binding to retinoid nuclear receptors (RARs) and retinoid X receptors (RXRs) in the nucleus
of target cells. Ligand-dependent RARs and RXRs form heterodimers that
bind to RA response elements (RAREs) on many genes, thereby modulating
transcriptional activity. Both RARs and RXRs belong to the superfamily
of nuclear receptors. RARs are activated by all
trans-RA and
9-cis-RA, whereas RXRs are only
activated by 9-cis-RA. Three isotypes
of RAR, ,
and
, encoded by distinct genes (for reviews, see
Refs. 15, 19) have been identified. Retinoid receptors consist of a
DNA-binding domain that contains Zn2+ finger motifs, a
ligand-binding domain, a ligand-independent transcriptional activation
domain, a ligand-dependent transcriptional activation domain, a
dimerization domain, and an F region of unknown function (for a review,
see Ref. 18). Through these various domains, RARs interact with other
transcriptional and signaling factors, including CBP/p300 (14),
activator protein-1 (32), TFIIH (31), and
TAFII135 (24).
Retinoids have pleiotropic effects in many target organs including the
lung. Vitamin A deficiency is associated with squamous metaplasia of
the respiratory epithelium. Clinical studies in premature infants
demonstrated a correlation between low serum levels of vitamin A and
chronic lung disease after respiratory distress syndrome (33). A
previous study (23) demonstrated that RA influences fetal lung
morphogenesis and differentiation. All three isotypes of RAR mRNAs are
expressed in pulmonary tissues during fetal development (22). In situ
hybridization analysis showed that RAR- was expressed in the
epithelium of proximal bronchi in day
14.5 postconception embryos, whereas
RAR-
and -
mRNAs were expressed rather weakly and homogeneously
in developing lung tissue (9). RA treatment of both human and rat fetal
lung explants in culture altered surfactant protein (SP) and mRNA
concentrations (3, 6, 11, 25). In human lung explant, RA
reduced SP-A and SP-C mRNA levels. In contrast, all
trans-RA increased SP-B mRNA levels in
a concentration-dependent manner, with the maximum increase observed at
3 µM (25). In vitamin A-deficient animals, fetal lung weight was
significantly decreased in association with decreased
phosphatidylcholine content, a marker of respiratory epithelial cell
differentiation (22). Mice bearing null mutations in both RAR-
and
RAR-
displayed some of the organ defects, including hypoplastic
lungs (23), providing further support for the role of RARs in lung
morphogenesis.
Pulmonary surfactant is a complex mixture of lipids and proteins that reduces surface tension at the air-liquid interface in the alveoli. Surfactant lipids are synthesized primarily by alveolar type II epithelial cells and are stored in lamellar bodies that are secreted into the air space. SP-A, SP-B, SP-C, and SP-D are also synthesized primarily by type II or bronchiolar epithelial cells and play critical roles in maintaining stability of the surfactant layer (SP-B and SP-C) and in host defense (SP-A and SP-D). The mechanisms by which RA and its RARs/RXRs influence surfactant homeostasis in type II epithelial cells in the respiratory epithelium, especially at the level of gene transcription, are largely unknown.
SP-B is a 79-amino acid amphipathic peptide produced by the proteolytic cleavage of SP-B proprotein (proSP-B) by type II epithelial cells. The SP-B peptide is stored in lamellar bodies and secreted with phospholipids into the airway lumen (for a review, see Ref. 36). SP-B is a critical component of the surfactant complex and is essential for the formation of tubular myelin and the stability and rapid spreading of surfactant phospholipids (36). Genetic defects in SP-B cause respiratory failure after birth in both humans and SP-B gene-targeted mice (7, 26, 27).
SP-B homeostasis is modulated at multiple levels. SP-B gene
transcription is influenced by thyroid transcription factor-1 (TTF-1)
and hepatocyte nuclear factor-3 (HNF-3) (4, 40). SP-B gene
transcription is further enhanced by cAMP and protein kinase
A-dependent phosphorylation of TTF-1 (42). Glucocorticoids stimulate
SP-B gene expression in both cell lines and lung explants (1, 2, 10,
34). Phorbol ester strongly inhibited SP-B gene expression (30, 35). At
the posttranscriptional level, SP-B mRNA stability is enhanced by
glucocorticoids and decreased by tumor necrosis factor- and phorbol
ester (28, 29, 38).
In the present study, both all trans- and 9-cis-RA enhanced transcription of the human and mouse SP-B promoters in human pulmonary adenocarcinoma cells (H441) and mouse lung epithelial cells (MLE-15). The H441 cell line was isolated from a human lung adenocarcinoma. The MLE-15 cell line was derived from mouse lung tumor cells immortalized by the SV40 large T antigen in vivo (37). Both cell lines have been used extensively to characterize SP-A, SP-B, and SP-C gene transcription.
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MATERIALS AND METHODS |
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Cell culture. H441 cells were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum, glutamine, and penicillin-streptomycin. Cells were maintained at 37°C in 5% CO2-air and passaged weekly. The murine clonal respiratory epithelial cell line MLE-15 was propagated in HITES medium (37) containing 4% fetal bovine serum and maintained as above.
Plasmid constructs. The region from
+41 to 2240 of the human SP-B (hSP-B) promoter was generated by
PCR with synthetic oligonucleotide primers with the p
5'-2240
SP-B chloramphenicol acetyltransferase (CAT) construct as a template as
described previously (40). The upstream primer with the
Mlu I site was
5'-CGCACGCGTACCTGCAGGTCAACGGATCA-3'. The downstream primer
with the Xho I site was
5'-GCGCTCGAGCCACTGCAGCAGGTGTGACTC. The PCR products were digested
with Mlu I and
Xho I restriction enzymes and ligated
with Mlu
I-Xho I-digested pGL2-B luciferase reporter plasmids (Promega). The correctness of the hSP-B 2240 promotor
fragment (hSP-B-2240) luciferase reporter construct was confirmed by
DNA sequencing. The murine (m) SP-B promoter fragment
1797/+42
(mSP-B-1797) was subcloned in the pBLCAT6 reporter vector as described
previously (5). The human TTF-1 1.7-kb luciferase reporter gene was
made previously (13). Human RAR and RXR expression vectors
hRAR-
/pSG5, hRAR-
/pSG5, hRAR-
1/pSG5, and
hRXR-
/pSG5 were kindly provided by Dr. Pierre Chambon. Human
glucocorticoid-receptor (GR) expression vector pR5-hGR-
was kindly provided by Dr. Ronald M. Evans.
Transfection, luciferase, and CAT
assays. To determine the effects of all
trans-RA and
9-cis-RA on the hSP-B promoter
luciferase reporter constructs, transient transfection and luciferase
assays were performed as previously described (40, 41) with minor modification. Briefly, H441 cells were seeded at a density of 2 × 105 cells/well in 6-well plates.
The hSP-B reporter constructs (0.5 µg) were transfected into H441
cells by lipofectin transfection (GIBCO BRL). In each transfection, 0.5 µg of pCMV--gal plasmid was included for normalization of
transfection efficiency. For quantification of
-galactosidase
activity, one unit of optical density of
-galactosidase
in the protein extract was defined as hydrolysis of
o-nitrophenyl-
-D-galactopyranoside
that generates absorbance to 1 optical density unit at 420 nm at
37°C. After 2 days of incubation with various concentrations of all
trans- and
9-cis-RA, the cells were lysed and
luciferase activity assays were performed with the luciferase assay
system (Promega). The light units were assayed by luminometry
(monolight 2010, Analytical Luminescence Laboratory, San Diego, CA). In
RAR/RXR cotransfection assays, 0.5 µg of various RAR and RXR
constructs was cotransfected with 0.5 µg of the hSP-B reporter
constructs and treated with 10 µM
9-cis-RA. Each experiment was repeated
at least three times. Human TTF-1 promoter studies with the luciferase
reporter gene with RARs/RXR-
were performed as outlined above. No
effect of RA and RARs/RXR-
on expression of
-galactosidase
activity was observed in transfection assays in H441 cells.
Transient transfection study of the mSP-B-1797 was performed with the
calcium precipitation method. A mixture of mSP-B-1797 (0.67 pmol/well)
and pCMB--gal (1.25 µg/well) was used for transfection followed by
the addition of 10 µM 9-cis-RA for 2 days. Cell extracts were prepared with three freeze-thaw cycles, and
the pellets were resuspended in 50-100 µl of 0.25 M Tris, pH
7.8. CAT assays were performed as previously described (5, 41).
Chromatograms of
[14C]chloramphenicol
and its acetylated derivatives were quantitated with a Molecular
Dynamics phosphorimager (Storm 680).
RT-PCR. Total RNA was purified from H441 cells treated with 10 µM 9-cis-RA for 0 and 28 h following the procedures described previously (39). The quality of RNA samples was assessed on 1% agarose gel after ethidium bromide staining. Thirty micrograms of total RNA were reverse transcribed with the oligo(dT) primer (NEN) by superscript RT enzyme (GIBCO BRL) in the presence of deoxynucleoside triphosphate and first-strand buffer (GIBCO BRL). Five micrograms of reverse transcripts were amplified in 30 cycles of PCR with a SP-B primer pair corresponding to exons 8 and 10 (upstream primer, 5'-GGTCGCCGACAGGAGAATGGCTGC-3'; downstream primer, 5'-AAGGTCGGGGCTGTGGATACACTG-3'). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a control, and the same reverse-transcribed cDNAs were used for PCR with a GAPDH primer pair (upstream primer, 5'-CAGAAGACTGTGGATGGCCCC-3'; downstream primer, 5'-GTCCACCACCCTGTTGCTGTAGCC-3'). Five micrograms of reaction products were separated on 1% agarose gel before being stained. Intensities of the PCR product bands were quantitatively analyzed by an IS-1000 Digital Imaging System (Alpha Innotech, San Leandro, CA).
Immunohistochemistry. H441 or HeLa
cells were seeded onto Permanox chamber slides (Fisher) at densities
ranging from 104 to
105 cells/chamber (2 chambers/slide) as described previously (12). For immunostaining of
SP-B, RAR, and RXR proteins, slides were pretreated with 0.1 M PBS
containing Triton X-100, pH 7.4, plus 5% goat serum for 2 h at room
temperature before incubation with a 1:500 dilution of RAR and RXR
rabbit polyclonal antibodies (Santa Cruz Biotechnology, Santa Cruz, CA)
or a 1:100 dilution of proSP-B polyclonal antibodies overnight. The
next day, the slides were washed five times in 0.1 M PBS with Triton
X-100 solution, and biotinylated goat anti-rabbit IgG was added to the
serum blocking solution (45 µl IgG/10 ml) for 30 min, followed by
five washes in 0.1 M PBS with Triton X-100 solution. The slides were
then treated with avidin-biotin reagent according to the directions in
the Vectastain Elite Kit (Vector Laboratories, Burlingame, CA). The
slides were visualized by a Nikon Microphot-FXA video system. For
transfection studies, 2 µg of the RAR- expression plasmid were
transfected into cells with the lipofectin transfection kit from
GIBCO BRL as previously described
(12). Immunohistochemical staining of the transfected cells was then
performed as described above.
Electrophoretic mobility shift assay.
An oligonucleotide corresponding to the hSP-B promoter 415 to
440 was synthesized, annealed, and purified. The oligonucleotide
was radiolabeled by [
-32P]ATP and
kinase and incubated with 100 ng of the purified RAR-
-glutathione S-transferase (GST) fusion protein as
suggested by the manufacturer (Santa Cruz Biotechnology). In the
absence of RXRs, a relatively higher concentration of RAR is required
due to its low DNA-binding affinity. Antibody-recognizing RAR-
(1 µg) was used for supershift assay. An electrophoretic mobility shift
assay (EMSA) was performed by following the procedures previously
described (40).
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RESULTS |
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Dose-dependent stimulation of hSP-B promoter activity
by all trans- and 9-cis-RA. To test the effects of RA
on SP-B gene transcription, the hSP-B-2240 luciferase reporter
construct was transfected into H441 cells. Cells were treated with all
trans- or
9-cis-RA
(105 to
10
9 M). Both all
trans- and
9-cis-RA enhanced hSP-B-2240 activity (Fig. 1). Activation was observed at
10
8 M of both
9-cis- and all
trans-RA (~10% increase).
Significant activation was observed at
10
5 M as assessed by
one-way ANOVA (P < 0.02).
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RA induced endogenous hSP-B mRNA in H441
cells. Because the transcriptional activity of the
hSP-B promoter was stimulated by RA, the effects of RA on the
expression of endogenous hSP-B mRNA were assessed by RT-PCR (Fig.
2). H441 cells were treated with
9-cis-RA
(105 M) for 0 and 28 h.
Total RNAs were extracted from cells, reverse transcribed, and
amplified by PCR with an hSP-B-specific primer pair, with a
GAPDH-specific primer pair as a control. After 28 h of exposure to
9-cis-RA, SP-B mRNA was significantly
increased (P < 0.02 by paired
t-test). No significant stimulation
was observed in GAPDH mRNA (P > 0.15). The H441 cells were also treated with dexamethasone (50 nM).
SP-B mRNA increased 30- to 50-fold after 28 h of treatment (data not
shown), consistent with previous observations (28).
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Increased proSP-B staining after treatment with
9-cis-RA. H441 cells were treated for 48 h with
9-cis-RA
(105 M) and
immunohistochemically stained with anti-human proSP-B polyclonal
antibody. Intracellular proSP-B staining of H441 cells was increased by
9-cis-RA (Fig.
3).
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RAR/RXR activation of the hSP-B
promoter. To assess the effects of RAR on hSP-B
promoter activity, three forms of human RAR (a, , and
)-RXR-
expression plasmids were cotransfected with the hSP-B-2240 luciferase
reporter construct into H441 cells. Cotransfection of RAR-
/RXR-
,
RAR-
/RXR-
, and RAR-
/RXR-
into H441 cells further increased
hSP-B 2.24-kb promoter activity, resulting in a seven- to ninefold
induction after treatment with 9-cis-RA
(P < 0.05 by one-way ANOVA; Table
1).
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Glucocorticoids are known to enhance SP-B mRNA in vivo and in H441 cells. To determine the potential role of the GR in SP-B gene regulation in H441 cells, a GR expression plasmid was cotransfected with the hSP-B-2240 luciferase reporter construct (Table 1). In the absence of a GR, dexamethasone (50 nM) slightly decreased the activity of the hSP-B-2240 luciferase reporter gene. Cotransfection with a GR also slightly decreased the activity of the hSP-B-2240 luciferase reporter gene in the absence of dexamethasone. Surprisingly, cotransfection with a GR in the presence of dexamethasone significantly repressed luciferase activity of the hSP-B-2240 from 100 ± 20 to 37 ± 4.5% of luciferase activity (P < 0.02 by one-way ANOVA).
Identification of RAREs on the hSP-B
promoter. In the region of 500 to
218 of
the hSP-B promoter, a sequence (
440 to
415) resembling a direct repetition of RARE (core motif,
A/GGG/TTCA) was identified (Fig.
4A).
This oligonucleotide, Ba-wt (
415 to
440), was synthesized
and incubated with the purified RAR-
-GST fusion protein.
Interestingly, three specific RARE-RAR-
complexes were detected by
EMSA, and an antibody recognizing RAR-
supershifted all three
complexes (Fig. 4B). In the promoter
deletion studies, activity of a hSP-B promoter (hSP-B-500) containing
this RARE was significantly enhanced by cotransfection with
RAR-
/RXR-
and 9-cis-RA
treatment as assessed by luciferase reporter assay and one-way ANOVA
(P < 0.02). A promoter construct
(hSP-B-375) lacking the RARE sequence was completely unresponsive
to RAR-
/RXR-
and 9-cis-RA
stimulation (Fig. 4C).
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Immunohistochemical detection of RAR and RXR proteins
in H441 and HeLa cells. Immunohistochemical staining of
H441 cells was performed with distinct antibodies recognizing the ,
, and
isotypes of RAR and RXR. RAR-
and -
and RXR-
were
detected in the nuclei of H441 cells (Fig.
5A),
whereas RAR-
and RXR-
and -
were not detected. In contrast,
HeLa cells were stained by antibodies recognizing RAR-
and -
and
all three forms of the RXR isotype (Fig.
5B). In both HeLa and H441 cells,
RAR and RXR staining was stronger in the nuclei than in the cytoplasm. Although RAR-
was not detected in either H441 or HeLa cells, RAR-
was readily detected after transfection with the hRAR-
expression
plasmid in both cell lines.
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9-cis-RA stimulates the activity of the mSP-B promoter
in MLE-15 cells. The effect of RA on the reporter
construct consisting of the mSP-B-1797 (5) was tested in MLE-15 cells.
9-cis-RA (105 M) activated the
mSP-B-CAT 1797-bp reporter construct to a similar extent as the hSP-B
2240 construct (P < 0.02 by paired
t-test; Fig.
6).
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9-cis-RA does not alter hTTF-1 promoter activity in H441 cells. SP-B gene transcription is strongly influenced by TTF-1. Previously, immunohistochemical and in situ hybridization studies (13, 17) demonstrated that TTF-1 expression was colocalized with SP-B in both human and mouse lungs. TTF-1 is also expressed in H441 and MLE-15 cells where it regulates SP-B gene transcription. To test the possibility that the effects of RA on SP-B expression were mediated by changes in TTF-1 gene transcription, the effect of RA on the activity of the human TTF-1 promoter region 1-1,700 bp was assessed. Cotransfection of RAR/RXR and GR had no effect on the hTTF-1 1.7-kb construct in the presence or absence of RA and dexamethasone (P > 0.1 by paired t-test; Fig. 7).
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DISCUSSION |
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In the present work, 9-cis-RA
stimulated the transcriptional activity of hSP-B and mSP-B gene
promoters in both human H441 and mouse MLE-15 cell lines. The
observation that relatively high doses of RA were required for hSP-B
promoter activation is consistent with a previous study (25) regarding
the effects of RA on SP-B mRNA expression in cultured human fetal lung
explants. 9-cis-RA also significantly
enhanced endogenous SP-B mRNA expression and SP-B protein accumulation
in H441 cells (Figs. 2 and 3). The present study also demonstrated that
cotransfection of all three RAR isotypes in combination with RXR
further enhanced RA treatment-dependent transactivation on the hSP-B
promoter, supporting the concept that the effects of RA are mediated by
RAR/RXR activation of the SP-B promoter. Detection of RAR ( and
)
and RXR (
) expression in H441 cells and the developing respiratory
epithelium in vivo also supports their potential roles in the
regulation of respiratory epithelial cell gene expression.
The observation that RA enhanced SP-B mRNA and protein expression in
H441 cells is consistent with previous findings from a study (25) of a
human fetal lung explant culture. The RA-dependent induction in SP-B
mRNA and protein is likely to be mediated, at least in part, by direct
interaction of RAR with the SP-B gene promoter to enhance SP-B gene
transcription. An RARE mediating the effects of RA on SP-B
transcription was localized in the region 415 to
440 on
the hSP-B promoter by EMSA. Deletion of this RARE resulted in loss of
RA stimulation in the transient transfection studies, supporting the
concept that RA and RAR/RXR heterodimers exert their effects directly
on the hSP-B promoter. Although both TTF-1 and HNF-3
stimulate the
hSP-B promoter, TTF-1 had a much stronger stimulatory effect (six- to
sevenfold) on the hSP-B promoter than HNF-3
(around twofold
stimulation) (42). The potential RAR sites were in close proximity to
the distal TTF-1 clustered sites (40). We therefore tested whether RA
enhances TTF-1 transcription, which would be more likely to enhance
SP-B transcription than HNF-3
, which is much less active on the SP-B
promoter. In contrast, cotransfection of RAR/RXR with the TTF-1
promoter construct did not alter its activity, although it remains
possible that RA may alter TTF-1 expression or activity by other
mechanisms. For example, a recent study (16) demonstrated that the
nuclear localization of TTF-1 and HNF-3
was affected by phorbol
ester.
The distribution of RARs in developing fetal mouse lung was determined
by in situ hybridization (9). Although RAR- was expressed in the
epithelium of proximal bronchi in day
14.5 postconception embryos, RAR-
and -
mRNAs
were expressed homogeneously, even though weakly, in lung tissue (9).
The critical roles of RAR-s in lung organogenesis were revealed by RAR
gene double-knockout mice (23). In these mice, both the right and left
lungs were either absent or markedly hypoplastic, indicating that RARs
are required for normal lung formation. H441 cells share many features with bronchiolar respiratory epithelial cells from the distal conducting airway. The presence of RAR-
and -
and RXR-
in H441 cells is consistant with their origin from distal respiratory epithelium and suggests their possible roles in bronchiolar cell differentiation and cell-type lineage maintenance.
Analysis of the GR-deficient mice revealed that a GR is required for lung maturation and perinatal survival (8). The GR-deficient mice die after birth of respiratory failure that is caused by a lack of inflation of the lung. However, SPs, including SP-B, are detected in the lung from the GR-deficient animals. In a previous study (28), dexamethasone stimulated SP-B mRNA and protein in H441 cells mediated by increasing SP-B mRNA stability. It has also been reported that dexamethasone stimulated SP-B transcription, although it remains unclear whether the effects of glucocorticoids are mediated directly by interaction of a GR with the SP-B promoter (1, 2, 10, 34). In the present study, dexamethasone repressed hSP-B-2240 transcription when cotransfected with a GR in H441 cells (Table 1). Thus the hSP-B-2240 region does not mediate the stimulatory effects of dexamethasone on SP-B expression in the H441 cell line.
RA plays a critical role both in lung organogenesis and in postnatal alveolarization (20, 21). All trans-RA caused a 50% increase in the number of alveoli in postnatal rats (20). Treatment of dexamethasone inhibited the formation of alveoli. Treatment with RA prevented the inhibitory effects of dexamethasone on alveolarization (20). RA also reversed elastase-induced pulmonary emphysema in adult rats, consistent with the potential roles of RA in the growth and differentiation of lung parenchyma.
In summary, the present study demonstrates a direct stimulatory effect of RA and RAR/RXR on SP-B gene transcription. RA and RAR/RXR increased SP-B gene transcription, mRNA accumulation, and SP-B synthesis in vitro.
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ACKNOWLEDGEMENTS |
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We thank Dr. Susan Wert for assistance with photomicroscopy and Dr. Tim Weaver for providing proSP-B antibody. We thank Dr. Pierre Chambon for providing the retinoic acid-receptor and retinoid X-receptor plasmids and Dr. Ronald M. Evan for providing the glucocorticoid-receptor plasmid.
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FOOTNOTES |
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This work was supported by the American Lung Association (C. Yan) and National Heart, Lung, and Blood Institute Specialized Center of Research Grant HL-56387 (to J. A. Whitsett and C. Yan).
Address for reprint requests: C. Yan, Children's Hospital Medical Center, Division of Pulmonary Biology, TCHRF, 3333 Burnet Ave., Cincinnati, OH 45229-3039.
Received 15 October 1997; accepted in final form 14 April 1998.
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