1 Fetal and Neonatal Research Group, Department of Physiology, Monash University, Victoria 3800, Australia; and 2 Pulmonary and Critical Care Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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Our objective was to determine the effects of sustained alterations in fetal lung expansion on pulmonary elastin synthesis. In fetal sheep, lung expansion was either decreased between 111 and 131 days' gestation (term ~147 days) by tracheal drainage or increased for 2, 4, 7, or 10 days by tracheal obstruction, ending at 128 days' gestation. Lung tropoelastin mRNA levels were assessed by Northern blot analysis, total elastin content was measured biochemically, and staining of lung sections was used to assess the localization and form of elastic fibers. Tracheal obstruction significantly elevated pulmonary tropoelastin mRNA levels 2.5-fold at 2 days, but values were not different from controls at 4, 7, and 10 days; elastin content tended to be increased at all time points. A sustained decrease in lung expansion by tracheal drainage reduced pulmonary tropoelastin mRNA levels 2.5-fold; elastin content was also decreased compared with controls, and tissue localization was altered. Our results indicate that the degree of lung expansion in the fetus influences elastin synthesis, content, and tissue deposition.
elastin synthesis; fetus; lung development
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INTRODUCTION |
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THE SUCCESSFUL TRANSITION from intra- to extrauterine life is largely dependent on the lung developing into an efficient gas exchange organ by the time of birth. For this to occur, the lung must have developed a sufficiently large surface area to sustain gas exchange (via the development of thin-walled alveoli) and must be both structurally and biochemically mature. Elastin is a unique protein that is a major component of the lung extracellular matrix and is concentrated around the entrance of individual alveoli as well as in the walls of airways and blood vessels (17). The physical properties of elastin allow the expansion and recoil of the lung that are essential to its mechanical performance. In the developing lung, elastin deposition occurs at the apex of secondary septal crests during the process of alveolarization (4) and, before alveogenesis, occurs in the mesenchyme surrounding the developing distal airways (26). Evidence indicating that the synthesis and deposition of elastin into the extracellular compartment play an essential role in the structural development of the fetal lung is provided by the finding that a reduction or abolition of elastin expression impairs distal airway development (26) and alveolar formation (11). Thus it is important to identify factors that regulate elastin synthesis during lung development.
The synthesis of elastin in the lung and other tissues is thought to be regulated by a number of factors including corticosteroids, growth factors, cytokines, and certain vitamins (15, 16, 22, 24); however, little is known about the influence of mechanical forces on elastin synthesis in vivo. An in vitro study has shown that cyclical mechanical strain increases tropoelastin mRNA expression in cultured fetal rat lung cells (18). However, the relevance of this to the in vivo environment is unclear as this stimulus was also shown to stimulate surfactant protein C expression, which is inhibited by a sustained increase in expansion of the fetal lung in vivo (12).
It is well established that mechanical forces within the lungs during fetal life play an integral role in lung growth and maturation (7). In the fetus, the lungs are filled with a liquid that is secreted across the pulmonary epithelium into the future air spaces and leaves the lungs via the trachea. This liquid maintains the lungs in an expanded state and provides the tissue stretch that is essential for normal lung development (1). Alterations in fetal lung expansion not only alter the rate of lung growth but also influence structural maturation, including alveolar development (1, 20). Given the close association between elastin synthesis and alveolar development, as well as structural changes in the lung parenchyma induced by alterations in fetal lung expansion, we hypothesized that sustained alterations in the degree of fetal lung expansion would alter elastin synthesis and hence elastin content in the fetal lung. As elastin turnover is extremely slow (23), an alteration in elastin deposition during fetal development could affect respiratory function for many years after birth. Thus our aim was to determine the effect of sustained increases and decreases in lung expansion on elastin synthesis in the fetal sheep lung in vivo.
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METHODS |
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Experimental preparation. Fetal lung tissue was obtained from experiments performed previously on chronically catheterized fetal sheep in our laboratory (10, 19). Aseptic surgery was performed on pregnant ewes between 107 and 115 days of gestation (term ~147 days) under general anesthesia (1.5% halothane in O2-N2O, 50:50 vol/vol). Two large-diameter saline-filled catheters were inserted into the midcervical trachea of the fetus: one was directed toward the lungs, and the other was directed toward, but did not enter, the larynx. These two catheters were exteriorized and joined together to form an exteriorized loop that allowed the normal flow of tracheal fluid (9). The ewe and fetus were allowed to recover from surgery for at least 5 days before the start of experiments.
To increase fetal lung expansion, we obstructed the re-entrant tracheal catheter for 2 (n = 5 fetuses), 4 (n = 5 fetuses), 7 (n = 5 fetuses), or 10 (n = 5 fetuses) days, with all experimental periods finishing on day 128 of gestation. In a separate group of age-matched control fetuses (n = 5), the trachea was cannulated but remained unobstructed, allowing the normal flow of lung liquid. To reduce fetal lung expansion, we continuously drained lung liquid by gravity from the descending tracheal catheter for 20 days (111-131 days of gestation) into an external bag (n = 5). In age-matched control fetuses, the trachea was cannulated, but lung liquid was not drained (n = 5). At the end of the experimental periods, all ewes and fetuses were painlessly killed with pentobarbital sodium administered intravenously to the ewe. At postmortem, the lungs were removed from the fetus, and the left main bronchus was ligated before portions of the left lobes were removed and frozen in liquid nitrogen and stored atNorthern blot analysis. Tropoelastin mRNA levels in the lungs were quantified by Northern blot analysis by established techniques (12). We used an ovine-specific tropoelastin cDNA probe labeled with [32P]dCTP using a random-priming labeling kit (Pharmacia Biotech) and quantified by exposure to a storage phosphor screen for 24-48 h. The cDNA probe was cloned by RT-PCR from fetal sheep lung tissue using ovine-specific oligonucleotide primers (5'-TGTGTCTCCAGCTGCAGCCTG-3' and 5'-TCACTTTCTCTTCCGGCCACA-3') designed to amplify a 214-bp fragment from the 3'-end of the published coding sequence of ovine tropoelastin (28). Sequence analysis verified that the RT-PCR product was 100% homologous with the published coding sequence. We standardized the amount of RNA loading between lanes by stripping and rehybridizing the membranes with a 32P-labeled probe for 18S rRNA. The relative amounts of tropoelastin and 18S rRNA were quantified by densitometry, and tropoelastin mRNA levels were expressed as ratios of the corresponding 18S rRNA levels for each lane.
Quantitation of elastin content. We quantified elastin content in the lung samples using a modification of an established method (21). Briefly, 0.8-1.0 g of fetal lung tissue was microdissected to remove tubular structures (airways and blood vessels) >20 µm in diameter. This enabled us to focus on changes in elastin content within alveolar structures in the lung. The tissue was then reweighed and homogenized in 0.15 M NaCl, with a final volume of 10 ml, and the homogenate was divided equally for duplicate analysis. The homogenate was centrifuged at 2,600 g for 10 min, and the supernatant was removed. The remaining pellet was resuspended in 5 M guanidine hydrochloride and incubated at 25°C for 24 h and then centrifuged at 20,800 g for 20 min. The pellet was then extracted for a further 24 h in 5 M guanidine hydrochloride, as above, to remove all soluble proteins from the tissue extract. After guanidine hydrochloride treatment, the tissue extract was washed and resuspended in distilled water and autoclaved at 121°C to solubilize and remove collagen. The pellet was again centrifuged and washed with distilled water. The remaining tissue extract, now considered to be elastin, was made soluble by elastase digestion (porcine pancreas type III, 0.1 mg/ml in 0.02 M NaHCO3 buffer, pH 8.8; Sigma), and the resulting peptides were quantified by a standard protein assay (Bio-Rad). The intra- and interassay coefficients of variation were 8.7 and 13.1%, respectively. Amino acid analysis was performed (Auspep, Melbourne, Australia) on the guanidine and autoclave-resistant tissue extract to confirm that it had an amino acid composition consistent with that of pure elastin. In these samples, both cysteine and methionine were undetectable, which is consistent with the sample being pure elastin. In addition, we compared the amino acid composition of our sample to that of the predicted composition from the published cDNA sequence (28) by regression analysis and found that the amino acid compositions were significantly correlated (P < 0.0001, r2 = 0.79).
Histochemical analysis. Paraffin-embedded sections of lung tissue were stained using the Hart's resorcin-fuchsin stain for elastin and counterstained with tartrazine (0.25%) in saturated picric acid. These sections were then viewed by light microscopy, and images were captured with a digital camera.
Data analysis. Data are presented as means ± SE. In all Northern blots, each lane contained total RNA from a single fetus. The integrated density of the tropoelastin mRNA band was divided by that of the 18S rRNA band for each lane to adjust for minor loading differences between lanes. Comparisons were made between mRNA samples that were run on the same Northern blot, thereby exposing the mRNA to the same hybridization conditions and exposure times. Statistical analyses of all data were performed with Student's unpaired t-test, except when we compared differences in elastin content. This was performed using a one-way analysis of variance (ANOVA). Significant differences indicated by ANOVA were subjected to the Student-Newman-Keuls post hoc test to detect significant differences between individual group means. Statistical significance was taken at P < 0.05.
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RESULTS |
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Tropoelastin mRNA transcript. A single mRNA transcript of ~3.5 kb was detected for tropoelastin by Northern blot analysis, in agreement with a previous report in fetal sheep (29).
Responses to increased lung expansion.
After 2 days of increased lung expansion induced by tracheal
obstruction (TO), tropoelastin mRNA levels expressed relative to 18S
rRNA in lung tissue (33.9 ± 8.7 arbitrary units) were
significantly greater than in control fetuses (13.6 ± 1.7). After
4 days of TO, tropoelastin mRNA levels were similar to those in control fetuses (control, 14.9 ± 2.4 vs. 4-day TO, 16.6 ± 2.7), and
this was also the case at 7 days of TO (control, 8.3 ± 1.0 vs.
7-day TO, 9.6 ± 2.5) and 10 days of TO (control, 14.2 ± 2.6 vs. 10-day TO, 16.8 ± 1.7). Expressed as a percentage of control
values, pulmonary tropoelastin mRNA levels were significantly greater at 2 days of TO (249.8 ± 8.7%) but then declined to 111.7 ± 18.1% at 4 days, 115.1 ± 30.3% at 7 days, and 118.1 ± 11.7% at 10 days of TO (Fig. 1).
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Responses to decreased lung expansion.
After 20 days of decreased lung expansion, tropoelastin mRNA levels in
lung tissue were significantly lower than in control fetuses (reduced
lung expansion, 13.8 ± 1.9 vs. control, 31.5 ± 5.8).
Tropoelastin mRNA levels in treated fetuses were 43.7 ± 5.9% of
values in control fetuses (Fig.
2).
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DISCUSSION |
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This study has shown that a sustained increase in fetal lung expansion induced by TO causes a large but transient increase in tropoelastin mRNA levels at 2 days. However, by 4 days, mRNA levels for tropoelastin had returned to control levels and did not alter for up to 10 days of increased lung expansion. In accordance with the changes in tropoelastin mRNA levels in fetal lung tissue, the elastin content of the lungs tended to be elevated in response to increased fetal lung expansion. In contrast, 20 days of decreased lung expansion reduced both tropoelastin mRNA levels and elastin content of the lungs. Together, these findings demonstrate that sustained alterations in the basal degree of fetal lung expansion correspondingly alter tropoelastin expression, which can result in a change in the total elastin content of the lungs.
The transient nature of the increase in tropoelastin expression observed in response to a sustained increase in fetal lung expansion was a surprising finding. It is unknown why the increase in tropoelastin expression was not sustained throughout the period of increased lung expansion. However, it is interesting that the time course for the changes in tropoelastin expression is very similar to the time course for the changes in pulmonary DNA synthesis rates in response to sustained TO (19). Whatever the explanation, it is evident from the large transient peak in DNA synthesis and tropoelastin expression at 2 days of TO that the stretch stimulus applied to responding cells is maximal at this time; we have recently observed similar results for the expression of the calmodulin-2 gene (5). One possible explanation for the transient nature of this response is the differential process by which the lung expands during extended periods of TO, thereby altering the stimulus provided to lung cells. We have previously shown that, over the first day of TO, fetal lung luminal volume increases approximately twofold, from ~30 to ~55 ml/kg (19). However, between days 1 and 2, the increase in lung expansion temporarily ceases, and lung volume does not increase further until after day 2; the lungs then continue to expand again until day 7, when they reach a maximum volume of ~95 ml/kg (19). Further expansion does not occur, presumably owing to the structural limits imposed by the chest wall. Our interpretation of these changes in lung volume is that over the first day of TO, the lung expands to a limit imposed by the structural framework of the lung tissue, and further expansion (i.e., between days 2 and 7) is dependent on remodeling of this framework. As the majority of lung cells are attached to, and closely interact with, this structural framework, it is likely that the stretch stimulus is maximal when the structural framework is initially stretched to its limit. However, after this initial 2-day period, extension or remodeling of the framework, perhaps due to increased collagen (19) and elastin synthesis, is unlikely to impose the same level of mechanical load to the same number of lung cells as the initial period of lung expansion (days 0-2).
Our finding that a sustained reduction in lung expansion decreased tropoelastin expression, whereas an increase in lung expansion stimulated tropoelastin expression, demonstrates the sensitivity of elastin synthesis to sustained alterations in fetal lung expansion. In contrast to an increase in fetal lung expansion induced by TO, continuous lung deflation suppressed tropoelastin expression for up to 20 days. This most likely results from the large decrease in the basal degree of lung expansion, and it is likely that the suppression of tropoelastin expression will be sustained for as long as the lung continues to be deflated. The finding that elastin staining is reduced in hypoplastic human fetal lungs associated with oligohydramnios (6) is consistent with this suggestion; the lung hypoplasia that is associated with oligohydramnios most probably results from a prolonged reduction in fetal lung expansion (2, 8).
As sustained alterations in fetal lung expansion have a profound influence on alveolar development (1, 20) and because alveolar formation is closely associated with pulmonary elastin synthesis during normal lung development (3), we hypothesized that elastin synthesis would change in parallel with changes in alveolar development. In support of our hypothesis, the transient increase in tropoelastin expression at 2 days of TO is consistent with the increase in alveolar number observed after 2-4 days of TO (20). Furthermore, the decrease in tropoelastin expression to control levels at 4 days of TO coincides with the absence of a further increase in alveolar number between 4 and 10 days of increased lung expansion (20). Although alveolar numbers do not increase between 4 and 10 days, the luminal surface area does, suggesting that elongation of the interalveolar septa has occurred (20). Also, the finding that elastin synthesis and content, as well as alveolar number (1), are reduced in response to sustained reductions in lung expansion is consistent with the concept that alveolarization and elastin synthesis are closely related.
Our inability to detect a statistically significant increase in pulmonary elastin content following increases in lung expansion, despite a large increase in tropoelastin expression, most probably indicates that the observed transient increase in tropoelastin expression yielded only a small increase in elastin content relative to the total amount of elastin preexisting in the lung. Much of the elastin synthesis and elastic fiber deposition is concentrated in the vasculature and conducting airways where changes, if present, were too subtle to measure. In contrast, the sustained reduction in tropoelastin expression induced by reduced lung expansion resulted in a reduction in elastin content compared with control animals. We consider that this reduction in elastin content resulted from the associated reduction in elastin synthesis, although it is possible that an increase in elastin metabolism contributed to the decrease in content.
In addition to alterations in elastin expression and content resulting from changes in fetal lung expansion, we observed changes in elastin deposition and secondary septal crest formation in lungs from fetuses with a sustained reduction in lung expansion. In these fetuses, elastin was laid down in a disorderly manner in the alveolar walls and at focused points where secondary septal crests would be expected to form; this observation is consistent with the suggestion that septation is inhibited in these animals. In contrast, in fetuses exposed to increased lung expansion, elastin deposition occurred predominantly at the tips of septal crests, as in control fetuses. Thus it appears that the increase in alveolar numbers induced by an increase in fetal lung expansion (20) is associated with normal elastin deposition within the secondary septal crests. These findings suggest that sustained stretch of the lung prenatally is important for the correct laying down of elastic fibers and for alveolar formation. The observation that elastin deposition in pulmonary arteries and large airways does not appear to be altered between the groups suggests that changes in lung expansion late in gestation primarily affect elastin synthesis in the alveolar region of the lung.
In accordance with the findings of our present study, previous studies
have shown that phasic mechanical strain increases tropoelastin mRNA
expression in cultured fetal rat lung cells (18).
Similarly, an apparent increase in elastin content has been reported in
human fetuses with laryngeal atresias, which cause an accumulation of
lung liquid and increased levels of lung expansion (27).
Furthermore, mechanical stress-dependent changes in elastin synthesis
have been shown in pulmonary artery segments tonically stretched in
vitro (25), suggesting a major role for mechanical forces
in the regulation of elastin synthesis in different tissue and cell
types. The mechanisms by which alterations in lung expansion alter the
expression of elastin in the lung are unknown but are likely to
involve various complex cell-matrix interactions. For example, it is
possible that mechanical forces could directly alter the transcription
of a gene by deformation of the nucleus via cytoskeletal elements
(13). Elastin expression may also be altered by various
soluble mediators such as growth factors released from surrounding
cells. It has been suggested that alveolar epithelial cells have the
ability to regulate lung fibroblast tropoelastin expression via an
unknown soluble factor (14). The influence of alterations
in lung expansion on a number of growth factors thought to play a role
in the regulation of tropoelastin synthesis is unknown. However,
transforming growth factor (TGF)-1 is unlikely to be involved,
as pulmonary TGF-
1 mRNA levels are increased only at 10 days of TO
(M. J. Wallace, unpublished observation) and do not coincide
with the transient increase in tropoelastin expression observed at 2 days of TO. Whatever the mechanism, the finding that sustained
alterations in lung expansion in the fetal sheep can affect elastin
expression is important for understanding normal lung development. In
particular, the apparent relationship between alterations in elastin
synthesis and alveolar development may have implications for infants
born with lung hypoplasia as well as preterm infants who may be born without having experienced normal levels of lung expansion during alveolar development.
A limitation of our study was an inability to distinguish between the effects of altered lung expansion on elastin expression in different structures within the lung parenchymal tissue such as blood vessels, airways, and alveolar structures. This is because assessment of tropoelastin expression was based on Northern analysis of whole lung tissue. Inappropriate tissue fixation in some cases prevented us from performing in situ hybridization experiments at this time. We did, however, remove the larger airways and blood vessels from the tissue before measurement of elastin content to focus on the changes in elastin synthesis that occur in the distal gas-exchanging region of the lungs.
Our study shows that, in the parenchyma of the developing fetal lung, the prevailing physical environment affects tropoelastin expression and elastin synthesis. Increased lung expansion transiently stimulates tropoelastin expression. In contrast, a sustained reduction in fetal lung expansion reduces tropoelastin expression and content, and, although it still appears to be deposited in aggregates, these aggregates are not associated with secondary septal crests. These findings provide further evidence that the basal degree of lung expansion in utero is an important determinant of the growth and structural development of the lung.
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ACKNOWLEDGEMENTS |
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We are grateful to Alex Satragno for assistance with the surgical preparation of animals, to Alison Thiel for assistance with the Northern analyses, and to Dr. Marianne Tare for assistance in the measurement of airway and vascular diameters.
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FOOTNOTES |
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This study was supported by the National Health and Medical Research Council of Australia and by National Heart, Lung, and Blood Institute Grant HL-54049.
Address for reprint requests and other correspondence: B. J. Joyce, Dept. of Physiology, Box 13F, Monash Univ., Vic. 3800, Australia (E-mail: belinda.joyce{at}med.monash.edu.au).
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.
10.1152/ajplung.00090.2002
Received 26 March 2002; accepted in final form 4 December 2002.
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