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Department of Pediatrics and Obstetrics and Gynecology, Harbor-University of California Los Angeles Research and Education Institute, Torrance, California 90502
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Developing rat
lung lipofibroblasts express leptin beginning on embryonic day (E) 17, increasing 7- to 10-fold by E20. Leptin and its receptor are expressed
mutually exclusively by fetal lung fibroblasts and type II cells,
suggesting a paracrine signaling "loop." This hypothesized
mechanism is supported by the following experimental data:
1) leptin stimulates the de novo synthesis of surfactant
phospholipid by both fetal rat type II cells (400% · 100 ng
1 · ml1 · 24 h1) and adult human airway epithelial cells
(85% · 100 ng1 · 24 h1);
2) leptin is secreted by lipofibroblasts in amounts that
stimulate type II cell surfactant phospholipid synthesis in vitro;
3) epithelial cell secretions such as parathyroid
hormone-related protein (PTHrP), PGE2, and dexamethasone
stimulate leptin expression by fetal rat lung fibroblasts;
4) PTHrP or leptin stimulate the de novo synthesis of
surfactant phospholipid (2- to 2.5-fold/24 h) and the expression of
surfactant protein B (SP-B; >25-fold/24 h) by fetal rat lung explants,
an effect that is blocked by a leptin antibody; and 5) a
PTHrP receptor antagonist inhibits the expression of leptin mRNA by
explants but does not inhibit leptin stimulation of surfactant phospholipid or SP-B expression, indicating that PTHrP paracrine stimulation of type II cell maturation requires leptin expression by
lipofibroblasts. This is the first demonstration of a paracrine loop
that functionally cooperates to induce alveolar acinar lung development.
lung development; surfactant; type II cell; lipofibroblast
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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LIPID-LADEN LIPOFIBROBLASTS were first identified as a morphologically distinct cell type in fetal and neonatal rat lung in 1970 (8). Both lipofibroblasts and adipocytes originate from mesoderm and are physically distinguished by the presence of large pools of triglyceride stores in their cytoplasm (11). The metabolism of lipid by these two cell types is also strikingly similar with respect to their lipogenic pathways, which are regulated by the same signal transduction pathway (11). Mature adipocytes express leptin, a 16-kDa cytokine product of the obesity (ob) gene (30). Fetal lung lipofibroblasts produce fibroblast pneumonocyte factor (FPF), a 10,000 to 20,000 molecular weight peptide that stimulates surfactant phospholipid synthesis by fetal type II cells (17). Differentiation of both cell types is stimulated by glucocorticoids (17, 33) and downregulated by androgens (10, 12). Furthermore, previous studies from our laboratory had suggested that lung epithelial cell secretions such as PGE2 (28) and parathyroid hormone-related protein (PTHrP; see Ref. 29) stimulate type II cell-fibroblast interactions via a soluble fibroblast growth factor of unknown identity. These observations, combined with the similarities between adipocytes and lipofibroblasts, and the recent reports that leptin is expressed in developing lung (9, 30) prompted us to investigate the possible role of leptin as a lipofibroblast growth factor that might stimulate fetal lung development.
It has long been recognized that lung development is mediated by soluble paracrine growth factors that mediate epithelial-mesenchymal interactions (15). These signals are bidirectional (1, 23), and the earliest known signals originate from the epithelium (22). We had previously identified PTHrP as a fetal rat alveolar type II cell product that is expressed beginning in the glandular phase of fetal lung development (16) and stimulates type II cell differentiation indirectly by stimulating fetal lung fibroblast factors (14). PTHrP stimulates fibroblast maturation through a receptor-mediated signal transduction pathway involving the production of cAMP and inositol phosphate (14), both of which induce fibroblast differentiation into adipocytes (34). Based on these observations, we hypothesized that leptin mediates the paracrine effect of PTHrP on alveolar type II cell surfactant synthesis.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Reagents. Leptin (rat, human) and leptin antibody (rat, polyclonal) were acquired from Linco (St. Charles, MO). The leptin RIA kit was obtained from DSL (Webster, TX). PTHrP-(1---34) and PTHrP-(7---34) amide were obtained from Bachem (Torrance, CA). Dexamethasone and PGE2 were purchased from Sigma Biochemicals (St. Louis, MO).
Animals. Time-mated Sprague-Dawley rats [embryonic day (E) 0, the day of mating] were obtained from Charles River Breeders (Hollister, CA). These experiments were conducted in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.
Cell culture. WI-38 and H441 cells were obtained from the American Type Culture Collection (Rockville, MD).
Isolation of lipofibroblasts and type II cells from fetal lung. The following methods have been used extensively in our laboratory (6). Three to five dams were used per preparation. The dams were killed with an overdose of pentobarbital sodium (100 mg/ml ip), and the pups were removed from the uterus by laparotomy and kept on ice. The lungs were removed en bloc in a laminar flow hood using sterile technique and put into ice-cold sterile Hanks' balanced salt solution without calcium or magnesium. The solution was decanted, and 5 vol of 0.05% trypsin (Worthington) were added to the lung preparation.
The lungs were dissociated in a 37°C water bath using a Teflon stirring bar to physically disrupt the tissue. When the tissue had been completely dispersed in a unicellular suspension (~20 min), the cells were spun down at 500 g for 10 min at room temperature in a 50-ml polystyrene centrifuge tube. The supernatant was decanted, and the cell pellet was resuspended in MEM (GIBCO) containing 10% FBS to yield a mixed cell suspension of ~3 × 108 cells as determined by a Coulter particle counter (Hialeah, FL). The cell suspension was added to 75-cm2 culture flasks (Corning Glass Works, Corning, NY) for 30-60 min at 37°C in a CO2 incubator to allow for differential adherence of the fibroblasts (20). Fibroblasts were maintained in MEM until further processing.Preparation of type II cell cultures. The unattached cells from the above-described cell preparation were transferred to another 75-cm2 culture flask for an additional 60-min period. After this second culture period, the medium and nonadherent cells were removed from the flask and diluted with 1 vol of culture medium. This diluted suspension was cultured overnight in a 75-cm2 flask at 37°C in a CO2 incubator to allow the type II cells to adhere (2). Type II cells were identified by their appearance in culture under phase-contrast microscopy, lamellar body content and microvillar processes, or by cytokeratin-positive staining.
Explant culture. Fetal rat lung tissue was cut into 1-mm cubes with a McIlwain tissue chopper (Brinkmann Instruments, Westbury, NY) and incubated in 0.5 ml Waymouth's MB-252/l medium containing penicillin (100 U/ml), streptomycin (100 U/ml), and fungizone (2.5 µg/ml) while rocking on an oscillating platform (3 cycles/min) in an atmosphere of 5% CO2-95% air at 37°C (25).
mRNA extraction. Total cellular RNA was isolated using previously described methods (5).
Semiquantitative RT-PCR. The appropriate cDNA fragments were amplified using 400 ng of total RNA from lung tissues or cells, avian myeloblastosis virus RT, and random hexamers and deoxyribonucleotides. The reactions were run at 42°C for 75 min and terminated by heating at 95°C for 5 min. Coamplification with glyceraldehyde-3-phosphate dehydrogenase cDNA was used as an internal standard. PCR was initiated by Taq DNA polymerase and allowed to proceed for 30 cycles with an annealing temperature of 50°C. The following primers were used in the RT-PCR assay: rat surfactant protein (SP) B (sense, 5'-TACACAGTACTTCTACTAGATG; antisense, 3'-ATAGGCTGTTCACTGGTGTTCC); human leptin (sense, 5'-CCTATCTTTTCTATGTCCAAGC; antisense, 3'-GTGAGGATCTGTTGGTAGACTG); human leptin receptor designed to detect all of the known isoforms (sense, 5'-TACTTTGGAAGCCCCTGATG; antisense, 3'-AAGCACTGAGTGACTGCACG); rat leptin (sense, 5'-TTATGTTCAAGCAGTGCCTATC; antisense, 3'-CATCCAACTGTTGAAGAATGTC); and rat leptin receptor(sense, 5'-ACCTTCAGTTCCAGATTCGA; antisense, 3'-TGAGATTGGTCTGATTTCCC). The identities of all RT-PCR products were confirmed by Southern blotting. mRNA expression was quantitated by densitometry (Eagle Eye; Stratagene).
Phospholipid assay. The rate of saturated phosphatidylcholine synthesis was determined as previously described (6) with modifications. Briefly, confluent monolayer cultures of fetal rat type II cells, H441 cells, or fetal rat lung explants were treated with leptin, PTHrP, leptin antibody, or PTHrP receptor antagonist and subsequently incubated with [3H]choline chloride (1 µCi/ml) for 4 h at 37°C in 5% CO2-95% air. Lamellar body fractions were prepared from the cells and tissues as described by Snyder et al. (21). To correct for procedural losses, fetal rat lung tissue was incubated with [U-14C]glycerol (10 µCi/ml, 10 mCi/mmol; NEN, Boston, MA) for 24 h, and lamellar bodies were prepared as previously described (21). This lamellar body preparation (10,000 dpm) was added to each sample before processing for [3H]phosphatidylcholine. Phospholipids were extracted from the lamellar body fractions by the method of Bligh and Dyer (3) and were dried under a stream of nitrogen at 50°C. The phospholipid extracts were mixed with 0.5 ml of an osmium tetroxide solution (70 mg/100 ml carbon tetrachloride) and reacted for 15 min at room temperature (26). The reaction mixture was dried under a stream of nitrogen at 60°C, and the dried extract was chromatographically separated by TLC in chloroform-methanol-water (65:25:4 vol/vol/vol; see Ref. 26). The phospholipids were subsequently scraped from the chromatography plates and analyzed for their radioactive content by liquid scintillation spectrometry.
Protein determination. Protein determination was made using the Bradford (4) dye-binding method.
Statistical analyses. ANOVA was used to compare data within experimental groups. The null hypothesis was rejected when P < 0.05 was not obtained.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Initially, we examined the expression and ontogeny of leptin by
fetal rat lung in the last third of gestation, during the phase of lung
development when the fibroblast and type II cell mature. As can be seen
in Fig. 1, the expression of leptin
increases progressively between E17 and E21, which corresponds to the
transition from the glandular (
E17) to the canalicular (E18 and E19)
and saccular (E20) stage of fetal rat lung development. The apparent decrease in leptin expression on E22 was observed consistently (n = 5). Leptin expression by E19 fetal rat lung
fibroblasts (Fig. 2, top) was
significantly increased by dexamethasone (8-fold), PTHrP (6-fold), and
PGE2 (6-fold), which are endocrine and paracrine factors
known to stimulate lipofibroblast development. Similar effects on
leptin expression were obtained (Fig. 2, bottom) by incubating human embryonic lung fibroblasts (WI-38) with these same
agonists. H441 human small cell carcinoma cells (Fig.
3) and E18 fetal rat type cells expressed
the leptin receptor, whereas expression of the leptin receptor was
faint in fetal rat lung fibroblasts and WI-38 cells, consistent with
the hypothesized paracrine nature of the leptin mechanism within the
alveolar acinus. Fetal rat lung fibroblasts cumulatively secrete leptin
in the culture medium over a 24-h period (Fig.
4), increasing from 23 ± 8 ng · ml1 · 4 h1 · 106 cells to 57 ± 12 ng · ml1 · 8 h1 · 106 cells and 97 ± 58 ng · ml1 · 24 h1 · 106 cells, equivalent to ~5
ng · ml1 · h1 · 106
cells; incubation of these cells with PTHrP increased secretion of leptin by greater than twofold more than the 6-h rate. Incubation of
fetal rat type II cells with leptin concentrations comparable to the
amounts we had observed being produced by the fetal rat lung
fibroblasts over a 24-h period stimulated the incorporation of
[3H]choline into lamellar body-saturated
phosphatidylcholine at 10, 50, and 100 ng/ml by 150-400% (Fig.
5). Leptin also stimulated choline
incorporation into lamellar body-saturated phosphatidylcholine by H441
cells, although the effect was lower than that of leptin on the fetal
type II cells, i.e., there was no effect at 10 ng/ml, 40% at 50 ng/ml,
and 85% at 100 ng/ml (Fig. 6). The
stimulation of surfactant synthesis by these cells of human adult lung
origin is evidence for the presence of functional leptin receptors on adult type II cells, which is consistent with the observed expression of leptin receptor mRNA by these cells (see Fig. 3).
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In subsequent experiments, we examined the interaction of PTHrP
and leptin in fetal rat lung explant culture. Incubation of E18 fetal
rat lung explants with leptin (200 ng · ml1 · 24 h1) or PTHrP
(5 × 107 M/24 h) significantly increased the
incorporation of [3H]choline into
[3H]phosphatidylcholine (>2-fold; Fig.
7). The concentration of leptin was
chosen based on its maximally effective dose in monolayer culture [see
effect of leptin on type II cells in monolayer culture (Fig. 4)] and
was doubled to compensate for tissue penetration. The PTHrP dose was
based on previous studies of its effect on surfactant synthesis in
explant culture (14). The stimulatory effect of PTHrP was
blocked by coincubation with leptin antibody (1:100 dilution). However,
the stimulatory effect of leptin was not blocked by coincubation with
the PTHrP receptor antagonist. Maintaining E18 fetal rat lung tissue in
explant culture for 3 days resulted in a 10-fold increase in leptin
mRNA expression (Fig. 8), consistent with
its developmental upregulation during this phase of lung maturation.
This increase in leptin mRNA expression was blocked by coincubation
with the PTHrP receptor antagonist [PTHrP-(7---34) amide, 5 × 106 M]. Incubation of E18 fetal rat lung explants with
leptin (200 ng · ml1 · 24 h1) or PTHrP (5 × 107 M/24 h) also
stimulated the expression of SP-B (Fig.
9); coincubation of PTHrP-treated E18
explants with leptin antibody (1:100 dilution) blocked the PTHrP
stimulation of SP-B expression. The same effect was observed when
leptin-treated explants were coincubated with leptin antibody (data not
shown), as expected. In contrast to this, coincubation of
leptin-treated explants with the PTHrP receptor antagonist (5 × 107 M/24 h) had no effect on leptin stimulation of SP-B
expression.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The hypothesized role of leptin as a paracrine mediator of the lung type II cell-fibroblast interaction resulting in surfactant synthesis was supported by our experimental results. Leptin and its receptor are expressed by fetal rat lung fibroblasts and type II cells, respectively, before the onset of type II cell maturation, beginning on E19-E20, and leptin expression is under both endocrine and paracrine control. Leptin stimulates both surfactant phospholipid and protein synthesis by type II cells by a PTHrP-dependent signaling pathway, based on the observation that the PTHrP receptor antagonist inhibits the developmental upregulation of leptin expression in explant culture; also, the leptin antibody blocks the PTHrP stimulation of surfactant phospholipid and protein expression, although the PTHrP receptor antagonist has no effect on (downstream) leptin-stimulated SP-B expression.
In the present series of experiments, we have observed that leptin mRNA expression in the developing fetal rat lung increases during the period of alveolar lung differentiation when pulmonary surfactant phospholipid synthesis is induced (E18-E20). Leptin expression appears to peak at E20 and then progressively declines on E21 and E22. This phenomenon has also been observed for FPF (18) and may be due to the thinning of the alveolar wall, which occurs during the process of alveolarization. The process of alveolar differentiation is a well-recognized hormonally regulated paracrine mechanism (17) that depends upon interactions between the type II epithelial cell and mesenchymal fibroblast. Type II cells elaborate PTHrP (29), which promotes the differentiation of the mesenchyme into lipofibroblasts in a manner similar to adipocyte differentiation, including the expression of key adipocytic enzymes, triglyceride uptake, storage, and secretion (11). These PTHrP-induced lipofibroblasts then apparently produce a soluble growth factor that stimulates type II cell surfactant phospholipid synthesis (14, 29) and SP-B expression, as shown in this study; the other surfactant proteins (SP-A, -C, and -D) were not examined, although they also play an essential role in surfactant metabolism. With these principles in mind, we hypothesized that the mature lipofibroblast, like the mature adipocyte, would express leptin, a secreted product of the mature adipocyte. Because leptin belongs to the interleukin-6 family of cytokines (32), and interleukin-6 stimulates the synthesis of pulmonary surfactant by type II cells (13), PTHrP-stimulated expression of leptin by lipofibroblasts provides a closed paracrine loop from the type II cell to the lipofibroblast and back to the type II cell.
It has long been recognized that alveolar type II cell differentiation
is dependent on mesenchymal-epithelial interactions (15),
which are mediated by low-molecular-weight soluble factors (7). Smith (18) was the first investigator to
identify a specific hormonally induced mesenchymal factor that
stimulated surfactant phospholipid synthesis over 20 years ago
(19), although the identity of this factor has remained
undetermined. He termed this differentiation factor FPF. We
subsequently discovered that FPF was downregulated by androgens
(6, 12), providing further evidence for a biological role
of FPF in the timing of lung development, since there is a spontaneous
sex difference in the rate of lung development and pulmonary surfactant
synthesis (6, 27) that is androgen dependent
(24). Leptin has many of the same characteristics as FPF:
1) its molecular weight (16,000) is within the
range previously reported for FPF (19); 2) it
is expressed by lung mesenchymal cells during fetal development in a
pattern like that reported for FPF (i.e., beginning in the canalicular
phase, peaking on E21, and then declining on E22; see Ref.
19); and 3) its expression is stimulated by
glucocorticoids (19) and inhibited by both androgens
(9) and transforming growth factor-
(25,
27). These similarities between leptin and FPF strongly support
their common identity. Their functional similarities are further
reinforced by their common cellular origins; leptin is produced by the
ob gene of the mature adipocyte (31), which
lung lipofibroblasts bear a strong resemblance to, both structurally
and functionally (11). FPF is also produced by
adepithelial lung fibroblasts (M. Post, personal communication). In
summary, leptin may be the long-sought-after soluble factor that
mediates the hormonal effects on fetal lung development, which govern
surfactant production.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-55268.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. S. Torday, Dept. of Pediatrics/OB-GYN, Center for Developmental Biology, RB-1, 1124 W. Carson St., Torrance, CA 90502 (E-mail: jtorday{at}prl.humc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 August 2000; accepted in final form 10 January 2001.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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 D.-M. Alexe, G. Syridou, and E. Th. Petridou Determinants of Early Life Leptin Levels and Later Life Degenerative Outcomes Clin. Med. Res., December 1, 2006; 4(4): 326 - 335. [Abstract] [Full Text] [PDF]
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D. A. Beuther, S. T. Weiss, and E. R. Sutherland Obesity and Asthma Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 112 - 119. [Abstract] [Full Text] [PDF]
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 M. C. Henson and V. D. Castracane Leptin in Pregnancy: An Update Biol Reprod, February 1, 2006; 74(2): 218 - 229. [Abstract] [Full Text] [PDF]
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 J. A. Hammond, K. A. Bennett, M. J. Walton, and A. J. Hall Molecular cloning and expression of leptin in gray and harbor seal blubber, bone marrow, and lung and its potential role in marine mammal respiratory physiology Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R545 - R553. [Abstract] [Full Text] [PDF]
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Y. Gao and J. U. Raj Parathyroid hormone-related protein-mediated responses in pulmonary arteries and veins of newborn lambs Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L60 - L66. [Abstract] [Full Text] [PDF]
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 J. S. Torday and V. K. Rehan Deconvoluting Lung Evolution Using Functional/Comparative Genomics Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 8 - 12. [Abstract] [Full Text] [PDF]
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S. T. Weiss and S. Shore Obesity and Asthma: Directions for Research Am. J. Respir. Crit. Care Med., April 15, 2004; 169(8): 963 - 968. [Full Text] [PDF]
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 M C Henson, K F Swan, D E Edwards, G W Hoyle, J Purcell, and V D Castracane Leptin receptor expression in fetal lung increases in late gestation in the baboon: a model for human pregnancy Reproduction, January 1, 2004; 127(1): 87 - 94. [Abstract] [Full Text] [PDF]
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S. A. Shore, Y. M. Rivera-Sanchez, I. N. Schwartzman, and R. A. Johnston Responses to ozone are increased in obese mice J Appl Physiol, September 1, 2003; 95(3): 938 - 945. [Abstract] [Full Text] [PDF]
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I. F. McMurtry Editorial: Introduction: pre- and postnatal lung development, maturation, and plasticity Am J Physiol Lung Cell Mol Physiol, March 1, 2002; 282(3): L341 - L344. [Full Text] [PDF]
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