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PubMed2003

Insulin-like growth factor-I receptor-mediated vasculogenesis/angiogenesis in human lung development.

The structural and functional development of the pulmonary system is dependent upon appropriate early vascularization of the embryonic lung. Our previous in vitro studies in a rat model indicated that insulin-like growth factor-I (IGF-I) is a potent angiogenic agent for fetal lung endothelial cells. To assess its role on human vascular lung development, we first examined the expression of IGF-I/II and IGF receptor type I (IGF-IR) in human embryonic and fetal lung tissues at 4-12 wk of gestation. Immunohistochemical and in situ hybridization studies revealed the presence of IGF-I/II-IGF-IR ligands and mRNA transcripts in embryonic lungs as early as 4 wk gestation. Immunotargeting using an anti-IGF-IR neutralizing antibody on human fetal lung explants demonstrated a significant blockade of IGF-IR signaling. Inactivation of IGF-IR resulted in a loss of endothelial cells, accompanied by dramatic changes in fetal lung explant morphology. Terminal transferase dUTP end-labeling assay and TEM studies of anti-IGF-IR-treated lungs demonstrated numerous apoptotic mesenchymal cells. Rat embryonic lung explant studies further validated the importance of the IGF-IGF-IR system for lung vascular development. These data provide the first demonstration of IGF-I/II expression in the human lung in early gestation and indicate that the IGF family of growth factors, acting through the IGF-IR, is required as a survival factor during normal human lung vascularization.

Animals↗
PubMed1999

EMAP II: a modulator of neovascularization in the developing lung.

Neovascularization is a key regulatory process in fetal growth and development. Although factors promoting growth and development of the pulmonary vasculature have been investigated, nothing is known regarding the molecular mechanisms that may counteract these stimuli. Endothelial monocyte-activating polypeptide (EMAP) II has recently been identified as an antiangiogenic factor in tumor vascular development. We postulated that EMAP II is a putative negative modulator of lung vascular growth. EMAP II mRNA and protein decrease fivefold (P < 0.01) as the developing lungs in the fetal mouse progress from having poor vascularization (day 14) to having complete vascular development at term (day 18.5). EMAP II protein expression continues to remain low throughout postnatal life and into adulthood, with the exception of a surge that correlates with microvascular maturation. Furthermore, through the use of in situ hybridization and immunohistochemistry, EMAP II is localized throughout the lung, with significant expression in the submyoepithelial area during the early stages of lung development when there is minimal vascular development. In contrast, EMAP II is distributed around the large vessels during the end of vascular development, suggesting that EMAP II modulates the neovascularization process. We speculate that EMAP II is a director of neovascularization in the developing lung.

Animals↗
PubMed1995

Role of fatty acids in lung development.

The role of maternal dietary fat in the regulation of fetal and newborn lung surfactant lipid synthesis has not been completely elucidated. Dietary fat can modulate cell membrane phospholipid fatty acid composition, resulting in altered membrane fluidity and affecting cellular functions, including binding to hormone receptors and the binding and activity of membrane-associated enzymes. Two examples are discussed that support the hypothesis that exogenous fatty acids modulate phospholipid synthesis in the lung. In the first example, long-chain unsaturated fatty acids were found to inhibit glucocorticoid receptor binding in L2 cells, suggesting that fatty acids may affect steroid responsiveness during different developmental stages of the lung. In the second example, a relationship was established between changes in membrane lipid composition during lung development and the activity of cholinephosphate cytidylyltransferase, the rate-limiting enzyme in phosphatidylcholine synthesis. The effects demonstrated in these in vitro studies will need to be confirmed by dietary studies of pregnant animals.

Animals↗
PubMed2003

Slit and robo: expression patterns in lung development.

First described as an axonal guidance cue through its repulsive effect on neurons expressing its receptor Roundabout (Robo), the Slit ligand has effects on cell migration, axon branching and elongation. Indirect evidence implicates Slit and Robo in lung development. We now demonstrate that Slit-2 and Slit-3 are developmentally regulated in embryonic murine lung. Immunohistochemistry demonstrates Slit-2 and Slit-3 expression by the pulmonary mesenchyme and airway epithelium. Robo-1 and Robo-2 are also expressed by the developing mesenchyme and airway epithelium. As lung development progresses, Robo-1 and Robo-2 expression localizes to only the airway epithelium. We conclude Slit/Robo are expressed in temporo-spatially adjacent domains suggesting interactive roles in pulmonary bronchiolar development.

Animals↗
PubMed1998

The effects of prenatal intraamniotic surfactant or dexamethasone administration on lung development are comparable to changes induced by tracheal ligation in an animal model of congenital diaphragmatic hernia: studies of lung glycogen content, elastic fiber density, and collagen content.

BACKGROUND/PURPOSE: A new noninvasive therapeutic strategy, which consisted of prenatal intraamniotic administration of porcine surfactant or dexamethasone, was previously used to prevent the functional and structural immaturity of lungs associated with congenital diaphragmatic hernia (CDH), and its effects on lung development were comparable with the changes induced by tracheal ligation (TL). The purpose of this study is to verify if this novel therapeutic modality has any effect in the elevated concentration of lung glycogen and altered contents of lung elastic fiber and collagen promoted by CDH. METHODS: A pilot study was performed to investigate in the rabbit model if the infused drugs in the amniotic cavity were aspirated by the CDH and non-CDH fetuses, and if there was correspondence between lung immaturity and high glycogen concentration in lung tissue. Experimental groups consisted of 50 pregnant rabbits that underwent surgery on gestational day 24 or 25 to create left-sided diaphragmatic hernias in 56 fetuses, which were divided in groups according to the procedures: CDH (n = 12), CDH plus TL (n = 16), CDH plus intraamniotic administration of Curosurf (40 mg, n = 12), and CDH plus intraamniotic administration of dexamethasone (n = 16). On gestational day 30, the fetuses were delivered by cesarean section, and 28 normal unoperated fetuses served as controls. The lungs were weighed and submitted to biochemical determination of glycogen, morphometric evaluation of elastic fibers, and colorimetric analysis of collagen. RESULTS: In all CDH and non-CDH fetuses of the pilot study, the amniotic content was massively aspirated into the lungs and trachea. There was an increase in lung glycogen content of fetuses at 24 days' gestation in comparison with 20-day gestational age fetuses, followed by a decrease in the near full-term fetuses. In the fetuses of the experimental groups, CDH decreased the lung weight to body weight ratios of lungs ipsilateral to the hernia. These changes were reversed by TL but not by intraamniotic administration of surfactant or dexamethasone. Lung glycogen concentrations in the lungs of CDH fetuses were significantly higher than those in the control group. These changes were reversed by intraamniotic administration of surfactant but not by dexamethasone administration or TL. In the lungs ipsilateral to the hernia, surfactant administration promoted a significant decrease in glycogen content to levels lower than control lungs. CDH promoted a decrease in the linear density of elastic fibers in both lungs, ipsilateral and contralateral to the hernia. This alteration was partially corrected by TL and surfactant administration, although dexamethasone administration had no effect. The concentrations of collagen in both lungs were increased significantly by CDH, and these alterations could not be reversed by TL. In the lungs ipsilateral to the hernia, intraamniotic administration of surfactant or dexamethasone promoted a significant decrease in the lung concentration of collagen but not to control levels. CONCLUSIONS: The positive effects of intraamniotic surfactant or dexamethasone administration on lung maturity of fetuses with CDH were observed. This therapy may be a substitute for TL.

Animals↗
PubMed2002

Thyroid transcription factor-1 expression during normal human lung development and in patients with congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Thyroid transcription factor-1 (TTF-1) was detected in human respiratory epithelial cells from 11 weeks of gestation. TTF-1 is involved in both lung morphogenesis and in the regulation of surfactant proteins. Recently, low expression of TTF-1 in the nitrofen rat model of congenital diaphragmatic hernia (CDH) was shown and restoration of this downregulation by antenatal glucocorticolds (CS) was reported. The aim of this study was to investigate the expression of TTF-1 as a marker of lung morphogenesis in normal human lung development and in age-matched controls of human lung specimen in hypoplastic lungs of human CDH and other forms of lung hypoplasia. METHODS: Immunohistochemistry by a monoclonal TTF-1 antibody was performed on paraffin sections of human fetal and neonatal lung tissues. The so-called developmental group (12 weeks' gestation to full term) included 47 lung specimens. The congenital hypoplasia group included 8 full-term CDH patients who died within 12 hours after birth, 3 full-term CDH patients who had antenatal CS therapy, and 4 full-term CDH patients after extracorporeal membrane oxygenation (ECMO) therapy. For comparison, 6 full-term born patients, who died of other forms of pulmonary hypoplasia, were used as comparative specimen. Immunohistochemical localization of TTF-1 was evaluated by light microscopy for 3 different areas of the airways including intrapulmonary bronchi, intermediate airways so-called terminal bronchioles, distal airways, and later sacculi and alveoli. RESULTS: Nuclear TTF-1 staining was observed in the progenitor cells of the developing bronchiolar cells early in the human lung developmental series. At full term, TTF-1 was expressed in both type II epithelial cells and in subsets of respiratory nonciliated bronchiolar epithelial cells in a pattern similar in all studied groups. No TTF-1 expression was detected at the level of the intrapulmonary bronchi. CONCLUSIONS: No difference in TTF-1 expression was observed in the developing early fetal and full-term neither in hypoplastic human lungs. This expression did not change with antenatal CS and postnatal ECMO treatment. Although TTF-1 appears to play an important role in lung morphogenesis, a pivotal role in human lung development is not likely.

Fetus↗
PubMed2005

Effects of viral respiratory infections on lung development and childhood asthma.

Viral infections are closely linked to wheezing in infancy, and those children with recurrent virus-induced wheezing episodes are at great risk for chronic childhood asthma. Infancy is a time of increased susceptibility to viral infections, and this stage is also characterized by pulmonary alveolar multiplication and extensive remodeling of the airways to accommodate growth. This coincidence, together with the observation that children with asthma can have structural lung changes and functional deficits at an early age, suggests that viral infections could adversely affect lung development. Inflammatory mediators induced by viral infection are known to have effects on the remodeling process, suggesting a plausible mechanism to support this theory. Furthermore, animal models of viral infection during lung growth and development suggest that developmental factors are important in determining the consequences of infection on long-term lung function. Greater understanding of the effects of viral infections on lung development and growth in early childhood might lead to the discovery of additional strategies for the prevention of recurrent wheezing and chronic asthma.

Animals↗
PubMed2003

Fetal cricotracheal manipulation: effects on airway healing, cricoid growth and lung development.

The last decade has seen significant advance in the surgical management of pediatric subglottic stenosis, which remains one of the most fascinating problems of the laryngotracheal complex (LTC). Refined techniques for operating on these fragile structures should reduce cricotracheal scarring to a minimum, thus avoiding a lot of severe postoperative complications in a tricky moment of laryngeal's growing up. Experimental works indicates that the LTC growth is variously affected by longitudinal anterior, posterior or lateral incisions and actually the indications for laringotracheoplasty or cricotracheal resection in children with subglottic stenosis are still unclear. Reports on fetal manipulation of cricotracheal tissues are lacking as well as early effects on airway healing, LTC growth and lung development. The aim of this study was to evaluate if the airway mucosal healing is regenerative and scarless after cricotracheal manipulation in fetuses of New Zealand White Rabbits (NZWRFs). The consequences of fetal incisions on the cricoid growth and lung development are also examined, in a group of 12 NZWRFs, manipulated at 25+/-1 days of gestational age. The does underwent halothane anesthesia and all received a bilateral longitudinal cricoidotracheotomy. Twenty sham-operated fetuses were submitted to a limited cervicotomy (control's group). At the time of retrieval (31+/-0.5 days), en bloc laryngotracheobronchial tree and lungs were collected and processed for histological and morphometric analysis. Parameters recorded included: 1) histological full-thickness examinations focusing on inflammation, foreign body reaction, fibrosis, neochondrogenesis; 2) morphometric analysis, including the fetal Subglottic Diameter (FSD), the fetal Subglottic Area (FSA), the Radial Alveolar Count (rAC) and Computer Assisted Morphometric Colorimetry (CAmc); 3)analysis of lung hypoplasia (LH) by means of lung weight/body weight (LW/BW) ratio, protein and DNA indexes; 4) finally, different fractions of lung tissue phospholipids for lung maturity assessment were studied. Student's t test, when indicated, was performed for statistical analysis (p <0.05 = significant). There was no maternal mortality in this study. Ten fetuses were available for a final evaluation (16.6% mortality). In one case only, an incomplete closure of the fetal cricoidotomy was seen and could be probably due to a technical mistake. Mean fetal subglottic diameter and area were respectively 0.13+/-0.05 mm and 3.15+/-0.45 mm2 in both groups. As well as in fetal dermal repair, regeneration of the airway cartilage and mucosa were complete and scarless. LW/BW ratio, DNA content and analysis of different fractions of phospholipids were similar in experimental vs. the control group. These findings suggest that the healing processes were fibrosis-free and without evidence of scars. A complete closure of the incisions was achieved without stenosis of the fetal subglottic region. In addition, it seems that the fetal cricoidotracheotomy doesn't interfere with the laryngeal function which coordinate the amount of liquid leaving the lungs via the trachea. In addition, only a small leakage of amniotic fluid is shown and this could be responsible for normal and mature lungs.

Animals↗
PubMed1987

Lung development in the fetal guinea pig: surfactant, morphology, and premature viability.

Guinea pigs demonstrate "precocious" physical and functional development, with newborns displaying open eyes, hair, self-feeding, and temperature regulation. In addition, morphologic lung development is precocious in the guinea pig, with advanced alveolarization taking place in utero. To explore whether pulmonary surfactant development is also advanced, and at what stage prematurely delivered guinea pigs are capable of survival, we delivered fetal guinea pigs at 2- to 3-day intervals from day 49 of gestation to day 69 (birth). These were examined for chronologic changes in lung morphology, lung tissue disaturated phosphatidylcholine, phosphatidylglycerol and glycogen content, and serum glucocorticoid and thyroid hormone levels. Other prematurely delivered guinea pigs were given brief postnatal resuscitation and their survival noted. We confirmed advanced morphologic lung maturation, yet found that surfactant development, with antecedent hormone peaks and glycogen depletion, occurs during the final 10-15% of gestation. Lung biochemical development is thus "on time" in the guinea pig, rather than "precocious" compared to other frequently studied laboratory animals. In addition, greater than 50% of fetal guinea pigs are capable of survival by 8 days prior to term, well in advance of premature survivability in other small-sized species.

Animals↗
PubMed2004

Bronchial branching correlates with specific glycosidase activity, extracellular glycosaminoglycan accumulation, TGF beta(2), and IL-1 localization during chick embryo lung development.

During organ differentiation, cell-extracellular matrix (ECM) interactions are required. The components of the ECM, such as glycosaminoglycans, fibronectin, laminin, and collagens, change in relation to cytokine and enzyme activity. Moreover, glycosaminoglycans (GAGs) are components of the ECM that play an important role in both cytokine regulation and cell activities. In this work we studied the accumulation of hyaluronic acid and chondroitin sulfate and heparan sulfate proteoglycans (PGs), beta-N-acetyl-D-glucosaminidase activity, the presence of transforming growth factor beta(2) (TGF beta(2)), and interleukin-1 (IL-1), and the localization of fibronectin, laminin, and collagen I and IV during the early stages of chick embryo lung development. We also determined the levels of hyaluronic acid, chondroitin sulfate, dermatan sulfate, and heparan sulfate GAGs and the activity of beta-N-acetyl-D-glucosaminidase with biochemical methods. Our data show that beta-N-acetyl-D-glucosaminidase activity increases in each cell, especially in the epithelial growth front at the emergence of each bronchial bud, where hyaluronic acid and IL-1 are located in the surrounding mesenchymal areas. Chondroitin sulfate and heparan sulfate PGs, fibronectin, laminin, and collagen I and IV are evident in the area near the basal membrane along the sides where the forming structures are stabilized. Biochemical data show that beta-N-acetyl-D-glucosaminidase activity increases in cells during lung development and is related to GAG decrease and to modifications of the nonsulfated/sulfated GAG ratio. These modifications could change cytokine activity and play an important role in bronchial branching development.

Animals↗
PubMed1995

Prenatal starvation, betamethasone and lung development in newborn rats.

This study examined the potential benefit of simultaneous transplacental betamethasone, which accelerates fetal lung maturation. Pregnant rats were placed in one of 4 groups: Control (C), fed ad libitum until term and given daily physiological saline injections from day 15 of gestation until term; Betamethasone (B), fed as group C but given daily physiological saline injections of 2.0 mg betamethasone/kg body weight from day 15 until term; Starved (S), given 50% rations from day 15 until term and injected as group C; Starved+Betamethasone (SB), fed as group S and injected as group B. Controls and group B did not differ in body or lung weight, protein or DNA, but group B lungs contained more lavageable and tissue surfactant. The S neonates weighed about 40% less than controls, with a proportional reduction in lung weight, DNA, protein or lavage and tissue phospholipids. Betamethasone may alleviate the impact of starvation on the developing lung by accelerating the process of alveolarization which was solved by caloric deprivation.

Animals↗
PubMed2003

Role for ETS domain transcription factors Pea3/Erm in mouse lung development.

During the development of the mouse lung, the expression of a number of genes, including those encoding growth factors and components of their downstream signaling pathways, is enriched in the epithelium and/or mesenchyme of the distal buds. In this location, they regulate processes such as cell proliferation, branching morphogenesis, and the differentiation of specialized cell types. Here, we report that the expression of Pea3 and Erm (or Etv5, Ets variant gene 5), which encode Pea3 subfamily ETS domain transcription factors, is initially restricted to the distal buds of the developing mouse lung. Erm is transcribed exclusively in the epithelium, while Pea3 is expressed in both epithelium and mesenchyme. Erm/Pea3 are downstream of FGF signaling from the mesenchyme, but their responses toward different FGFs are not the same. The functions of the two proteins were investigated by transgenic expression of a repressor form of Erm specifically in the embryonic lung epithelium. When examined at E18.5, the distal epithelium of transgenic lungs is composed predominantly of immature type II cells, while no mature type I cells are observed. In contrast, the differentiation of proximal epithelial cells, including ciliated cells and Clara cells, appears to be unaffected. A model is proposed for the role of Pea3/Erm during the dynamic process of lung bud outgrowth and proximal-distal differentiation, in response to FGF signaling. Our results provide the first functional evidence that Pea3 subfamily members play a role in epithelial-mesenchymal interactions during lung organogenesis.

Animals↗
PubMed2004

[Expression of telomerase reverse transcriptase and its significance in human fetal lung development].

OBJECTIVE: To investigate the expression and distribution of telomerase reverse transcriptase (hTERT) and its significance during the development of epithelial stem cells in human fatal lungs. METHODS: Human lung tissues were obtained at abortion from 37 fetuses 10-34 weeks of gestational age with parental consent, and the expression of hTERT in these tissues was examined by immunohistochemistry. RESULTS: In fetuses of 10 weeks old, hTERT was detected mainly in the epithelial cells of the proximal bronchi in the fetal lung, and migrated gradually to the distal bronchi as the lung developed. The hTERT expression level peaked at 17-20 weeks of gestation and then decreased over the period of alveolarization that occurred at about 25-26 weeks. In the later gestation period, strongly positive epithelial cells became concentrated in discrete patches near the basal membrane of the airway and scattered in only a few of the pulmonary alveoli. Morphologically, these cells resembled the basal cells and type II alveolar epithelial cells (AEC) or their progenitor cells. CONCLUSIONS: Telomerase expression and activity are hallmarks of the pulmonary stem or progenitor cells that maintain undifferentiated state and self-renewal capacity, and it plays a crucial role in the normal differentiation and regeneration of the bronchial and alveolar epithelial cells to maintain the epithelial integrity.

DNA-Binding Proteins↗
PubMed2000

Role of transcription factors in fetal lung development and surfactant protein gene expression.

Branching morphogenesis of the lung and differentiation of specialized cell populations is dependent upon reciprocal interactions between epithelial cells derived from endoderm of embryonic foregut and surrounding mesenchymal cells. These interactions are mediated by elaboration and concerted actions of a variety of growth and differentiation factors binding to specific receptors. Such factors include members of the fibroblast growth factor family, sonic hedgehog, members of the transforming growth factor-beta family, epidermal growth factor, and members of the platelet-derived growth factor family. Hormones that increase cyclic AMP formation, glucocorticoids, and retinoids also play important roles in branching morphogenesis, alveolar development, and cellular differentiation. Expression of the genes encoding these morphogens and their receptors is controlled by a variety of transcription factors that also are highly regulated. Several of these transcription factors serve dual roles as regulators of genes involved in early lung development and in specialized functions of differentiated cells. Targeted null mutations of genes encoding many of these morphogens and transcription factors have provided important insight into their function during lung development. In this chapter, the cellular and molecular mechanisms that control lung development are considered, as well as those that regulate expression of the genes encoding the surfactant proteins.

Animals↗
PubMed1986

Metabolism and function of platelet-activating factor in fetal rabbit lung development.

Previously, platelet-activating factor (PAF, PAF-acether, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) had been identified in association with a lamellar-body-enriched fraction of human amniotic fluid obtained from women in labor. In consideration of the fact that fetal lung is the source of lamellar bodies, we have investigated the capacity of the developing lung to synthesize PAF. The specific activity of the PAF biosynthetic enzyme, 1-alkyl-2-lyso-sn-glycero-3-phosphocholine: acetyl-CoA acetyltransferase, increased from 116 pmol/min per mg protein in day 21 fetal rabbit lung to 332 pmol/min per mg protein by day 31. Although this enzymatic activity in fetal kidney also increased, it never reached the level found in lung. In contrast, the actyltransferase activity decreased by 80% in fetal liver between days 21 and 31. The acetyltransferase activity in lung was primarily localized in the microsomal fraction (105 000 X g pellet); however a significant proportion of the activity was found in the 18 000 X g pellet. The specific activity of acetyltransferase in adult alveolar type II rat pneumonocytes was significantly higher than that of adult rat lung or rat alveolar macrophages, suggesting that type II cells make a significant contribution to the actyltransferase activity of lung tissue. PAF acetylhydrolase remained relatively constant throughout the gestation in all tissues. The concentration of PAF in the fetal lung increased by 3-fold from 12 to 35 fmol/mg protein, between day 21 and day 31 of development. The concentrations of the PAF precursors, 2-lyso-PAF (1-alkyl-2-lyso-sn-glycero-3-phosphocholine) and the 2-acyl derivative, were several orders of magnitude higher than the PAF concentration. The pulmonary glycogen content decreased from 163 at day 21 to 35 micrograms/mg protein at day 31 of gestation. We suggest that the increase in PAF concentration may participate in the regulation of glycogen breakdown in fetal lung as it does in perfused rat liver (Shukla, S.D., Buxton, D.B., Olson, M.S. and Hanahan, D.J. (1983) J. Biol. Chem. 258, 10212-10214). The formation of PAF in the developing lung and its secretion, in association with lamellar bodies, into amniotic fluid is discussed in relation to parturition.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1995

Effect of retinoids on fetal lung development in the rat.

We investigated the effect of retinoids on fetal lung development in the rat. The concentration of retinyl palmitate increased rapidly to a peak on day 17 of gestation and decreased to a minimum on day 21 of gestation; there was a slight increase after birth. Retinoid acid receptor (RAR)-alpha and -beta mRNA were detected in all samples obtained from perinatal and adult rat lung, and only a trace of RAR-gamma mRNA was detected in the fetuses on days 15, 17 and 19 of gestation and in the adults by reverse transcriptase-polymerase chain reaction. After a maternal retinol deficiency of 28 days' duration, fetal body and lung weights were significantly lower than those of controls; the concentrations of retinyl palmitate and phosphatidylcholine (PC) in the lung after a maternal retinol deficiency of 14, 21, or 28 days were significantly lower than those of controls. Expression of RAR-beta mRNA in the group with 28-day retinol deficiency was lower than in controls, that of RAR-alpha mRNA was increased and that of RAR-gamma mRNA was not influenced by retinol deficiency. The rate of choline incorporation into PC in fetal lung explants was significantly higher in the group treated with retinoic acid (RA) than in controls. RA enhanced the effect of epidermal growth factor on choline incorporation and prevented that of dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Trophic control of lung development by sympathetic neurons: effects of neonatal sympathectomy with 6-hydroxydopamine.

The onset of peripheral sympathetic neuronal function is thought to provide trophic regulatory signals for development of adrenergic target tissues. In the current study, we examined the effects on lung development of neonatal sympathectomy with 6-hydroxydopamine. The completeness of the lesion and effectiveness in reducing sympathetic input to the tissue were confirmed by direct measurement of norepinephrine levels and turnover. Despite the denervation, no evidence of beta-receptor up-regulation was found; in fact, receptor binding sites tended to be reduced throughout development. The cyclic AMP response to isoproterenol challenge was initially suppressed in the lesioned animals, but became supersensitive even in the face of reduced receptor binding capabilities. Evidence was also obtained for ontogenetic abnormalities in the ornithine decarboxylase/polyamine system, which is partially controlled by beta-adrenergic input and which regulates macromolecule synthesis in replicating and differentiating cells. Eventually, the alterations were reflected in aberrant developmental patterns of DNA, RNA and protein in the lung. These results indicate that sympathetic neurons influence the biochemical development of the lung and may serve to program permanently the relationships among receptor sites, receptor coupling to cellular function, and control of cell maturation.

Animals↗
PubMed1989

[The effect of betamethasone (celeston) on fetal lung development in rats].

The influence of betamethasone (celestone) was studied on the fetal lung development in pregnant rats of Wistar strain. It was shown that the drug was without effect, administered singly. After treatment of the pregnant rats for a period of 3 days with a dose of 0.100 mg/kg the content of the lung surfactant in their amniotic fluids was increased, manifested by an elevation of the threshold dilution (TD), determined by the method of the black foam film. Administration of two-fold higher dose did not cause quicker synthesis of surfactant. The morphological examination of the fetal lung showed that celestone accelerated the synthesis, maturation and secretion of surfactant and intensified differentiation of prealvelocytes of I and II types after the 18th day of the fetal development, which occurred a day earlier than in the control rats.

Animals↗