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PubMed1995

The effect of low amniotic pressure without oligohydramnios on fetal lung development in a rabbit model.

OBJECTIVE: Our purpose was to examine fetal lung development in reduced intraamniotic pressure without amniotic fluid loss. STUDY DESIGN: A circular portion of uterine wall measuring 1 cm in diameter was excised while the chorionic and amniotic membranes were left intact at the twenty-third day of gestation in New Zealand White rabbits. The chorionic and amniotic membranes herniated spontaneously through the defect. RESULTS: Amniotic pressure was significantly reduced after herniation. Lung weight/body weight ratios at term were significantly reduced in experimental fetuses compared with controls. Residual amniotic fluid volumes at term did not differ. Histopathologic examination of lung specimens showed that fetal lungs had not matured in the experimental group as fully as in the control group. CONCLUSION: This experimental study demonstrated that low amniotic pressure impaired fetal lung development, even without oligohydramnios.

Amnion↗
PubMedDate not supplied

Vitamin A and lung development.

Several lines of evidence suggest that vitamin A is involved in lung development. They are: 1) Dietary deficiency of the fat-soluble vitamin A results in squamous metaplasia of the tracheal and bronchial epithelium. 2) Infants with vitamin A deficiency have a high incidence of respiratory problems. 3) Levels of two intracellular proteins binding specifically retinol (vitamin A alcohol) and retinoic acid (vitamin A acid) change dramatically during perinatal lung development. 4) Prematurely born infants hospitalized for respiratory problems have low serum concentrations of retinol and retinol-binding protein. 5) Postnatal supply of vitamin A by parenteral alimentation may not be adequate, as large quantities of vitamin A are absorbed by the tubing. Careful assessment of vitamin A status in postnatal nutritional management of premature infants is desirable.

Cell Differentiation↗
PubMed1992

Mimicking low amniotic pressure by chronic pharyngeal drainage does not impair lung development in fetal sheep.

OBJECTIVE: The etiology of oligohydramnios-related pulmonary hypoplasia is not understood but is known to involve chronic lung liquid loss. We tested the hypothesis that low amniotic pressure in oligohydramnios disturbs the normal tracheal-amniotic pressure gradient to increase lung liquid loss and impair lung development. STUDY DESIGN: Chronic pharyngeal catheterization with drainage to the exterior was used in 15 fetal sheep to mimic reduced amniotic pressure at the upper airway in the presence of normal amniotic fluid volume. RESULTS: Pharyngeal pressures relative to amniotic pressures were negative in all drained fetuses (mean +/- SE -3.0 +/- 0.6 mm Hg), in contrast to positive pressures in controls (0.7 +/- 0.1 mm Hg). There was no significant difference in lung weight or deoxyribonucleic acid relative to body weight, or in lung morphometry, between 10 fetuses drained for 10 to 21 days and their control cotwins. CONCLUSION: Mimicking low amniotic pressure in the upper airway by chronic fetal pharyngeal drainage does not impair lung development in fetal sheep.

Amniotic Fluid↗
PubMed1992

Fetal breathing movements are not a good indicator of lung development after premature rupture of membranes and oligohydramnios--a preliminary study.

The effect of severe oligohydramnios (due to prolonged premature rupture of the membranes (PROM)) on breathing movements and lung development was studied longitudinally in 11 human fetuses. Prenatally, fetal breathing movements (FBM) were scored off-line from weekly, 1 h during ultrasound recordings (n = 47). In each recording, the incidence of FBM was scored according to 4 different methods. Postnatally, the cases were retrospectively assigned to a group with normal (n = 4), partially hypoplastic (n = 3), or hypoplastic (n = 4) lungs. Compared to control fetuses, the percentage of time spent breathing (%FBM) was low (2-5%) and did not increase with gestational age. Large inter-individual and intra-individual variations in the %FBM were found in all 3 diagnostic groups. Evaluation of the %FBM according to the 4 different methods revealed no significant differences between the 3 groups. We conclude that lung development is, at least partly, independent of the incidence of FBM. Furthermore, the analysis of FBM cannot reliably predict lung development in fetuses with oligohydramnios due to PROM.

Cross-Sectional Studies↗
PubMed1980

Metabolic adaptation in developing lung.

We have carried out studies using rat lung slices showing that the developing lung utilizes both glucose and fatty acids as oxidative substrates. Glucose oxidation to CO2 decreased at birth but showed higher activity after weaning. The activity of the pentose phosphate pathway also decreased postnatally. In contrast to glucose, the oxidation of palmitate and caprate to CO2 showed an increase in the immediate postnatal period. Cytochrome oxidase and carnitine palmitoyltransferase showed a parallel postnatal increase following the increase in fatty acid oxidation. Cytochrome oxidase activity in adult lung was approximately 30% of peak newborn values. Palmitate incorporation into total lipids was greatest at 18 to 19 days of fetal development, at which time the lung content of nonesterified fatty acids was highest.

Age Factors↗
PubMed2003

Regulation of postnatal lung development and homeostasis by estrogen receptor beta.

Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor alpha (ERalpha) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ERbeta is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ERbeta gene (ERbeta(-/-)) revealed decreased numbers of alveoli in adult female ERbeta(-/-) mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Platelet-derived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ERbeta(-/-) mice, and direct transcriptional regulation of these genes by ERbeta was demonstrated. This suggests that estrogens act via ERbeta in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ERbeta as a previously unknown regulator of postnatal lung development and homeostasis.

Animals↗
PubMed1998

Programmed cell death contributes to postnatal lung development.

The rat lung undergoes the phase of maturation of the alveolar septa and of the parenchymal microvascular network mainly during the third postnatal week. Speculating that programmed cell death may contribute to the thinning of the alveolar septa, we searched for the presence of DNA fragmentation in rat lungs between postnatal days 6 and 36 using the TUNEL procedure. The number of positive nuclei was compared at different days. We observed an 8-fold increase of programmed cell death toward the end of the third week as compared to the days before and after this time point. The precise timing of the appearance of the peak depended on the size of the litter. Double-labeling for DNA fragmentation (TUNEL) and for type I and type II epithelial cells (antibodies E11 and MNF-116), as well as morphologic studies at electron microscopic level, revealed that during the peak of programmed cell death mainly fibroblasts and type II epithelial cells were dying. While both dying cell types were TUNEL-positive, nuclear fragments and apoptotic bodies were exclusively observed in the dying fibroblasts. We conclude that programmed cell death is involved in the structural maturation of the lung by reducing the number of fibroblasts and type II epithelial cells in the third postnatal week. We observed that the dying fibroblasts are cleared by neighboring fibroblasts in a later stage of apoptosis, and we hypothesize that type II epithelial cells are cleared by alveolar macrophages in early stages of the programmed cell death process.

Aging↗
PubMed2025

Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.

Congenital Diaphragmatic Hernia (CDH) is a rare neonatal disorder causing diaphragmatic defects and cardiopulmonary hypoplasia, traditionally attributed to mechanical compression from organ herniation. However, emerging evidence suggests genetic mutations may independently impair lung development, prompting debate over CDH etiology. Here, we investigated the requirement of mitochondrial function guarded by LON peptidase 1 (Lonp1), a CDH risk gene, in either diaphragm or lung development. Lonp1 loss in skeletal muscles of the diaphragm led to its thinning and membranization, recapitulating the pathology of sac-type CDH. On the other hand, lung-specific inactivation caused severe hypoplasia with defective branching morphogenesis, independent of diaphragm anomalies. Molecularly, Lonp1 disruption dysregulated key transcription factors and signaling pathways known to be critical for early lung development. Our findings here revealed that mitochondrial defects contribute to the pathogenesis of CDH in an organ and cell type specific manner, opening new avenues for drug and therapeutic development.

CDH↗
PubMed1996

Cellular localization of messenger RNAs for insulin-like growth factors (IGFs), their receptors and binding proteins during fetal rat lung development.

To gain insight into the role of the insulin-like growth factors (IGFs) in regulating lung development, we have used in situ hybridization histochemistry (ISHH) to examine the ontogeny and sites of expression of IGF-I and IGF-II, IGF binding proteins (IGFBP-1 to IGFBP-6), and IGF cell surface receptors in fetal rat lung from 15 to 21 days of gestation. Both IGF-I and IGF-II mRNAs were expressed throughout the developmental period studied with little change in apparent abundance. IGF-I mRNA localized to mesenchymal cells, especially those surrounding airway epithelium, while IGF-II mRNA, which was somewhat more abundant, localized predominantly to epithelia. The type 1 IGF receptor, the receptor that likely mediates the actions of both IGFs, was expressed widely in virtually all cells, whereas the expression of the type 2 IGF receptor, thought to be involved in IGF internalization and degradation, was confined to the mesenchyme and medial layers of intrapulmonary vessels. As with the IGFs, there was little apparent change in the abundance of IGF receptor mRNAs through fetal development, and the type 2 IGF receptor mRNA was more abundant. The expression of IGFBPs changed significantly during lung development. IGFBP-2, -3, -4, and -5 were expressed from day 15 of gestation, but their sites of expression and ontogeny differed. IGFBP-2 mRNA expression was abundant and constant throughout gestation and was confined to proximal and distal airway epithelia. IGFBP-3 and IGFBP-5 also were expressed by proximal airway epithelia, but also exhibited significant expression in interstitial mesenchyme and in mesenchyme surrounding vessels. The abundance of both increased as gestation progressed (IGFBP-5 greater than IGFBP-3). IGFBP-4 mRNA was confined to interstitial mesenchyme and its abundance peaked at days 16 to 19 of gestation. We found no evidence for expression of either IGFBP-1 or IGFBP-6. We conclude that the expression of IGF-I, IGF-II, and the type 1 IGF receptor throughout gestation in the lung supports a role for the IGFs in lung growth and development. The complex pattern of IGFBP expression (differing sites and ontogeny of expression) suggests that the IGFBPs modulate IGF actions at specific target sites. Furthermore, because there is little change in the expression of IGFs or IGF receptor mRNAs during fetal lung development, regulation of IGFBP expression may be essential to the control of IGF actions during lung development.

Animals↗
PubMed2005

Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation.

Understanding how lung progenitor cells balance proliferation against differentiation is relevant to clinical disorders such as bronchopulmonary dysplasia of premature babies and lung cancer. Previous studies have established that lung development is severely disrupted in mouse mutants with reduced levels of the proto-oncogene Nmyc, but the precise mechanisms involved have not been explored. We show here that Nmyc expression in the embryonic lung is normally restricted to a distal population of undifferentiated epithelial cells, a high proportion of which are in the S phase of the cell cycle. Overexpression of NmycEGFP in the epithelium under the control of surfactant protein C (Sftpc) regulatory elements expands the domain of S phase cells and upregulates numerous genes associated with growth and metabolism, as shown by transcriptional microarray. In addition, there is marked inhibition of differentiation, coupled with an expanded domain of expression of Sox9 protein, which is also normally restricted to the distal epithelial compartment. By contrast, conditional deletion of Nmyc leads to reduced proliferation, epithelial differentiation and high levels of apoptosis in both epithelium and mesenchyme. Unexpectedly, about 50% of embryos in which only one copy of Nmyc is deleted die perinatally, with similarly abnormal lungs. We propose a model in which Nmyc is essential in the developing lung for maintaining a distal population of undifferentiated, proliferating progenitor cells.

Animals↗
PubMed2002

Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning in developing lung.

The lung has specific vascular patterning requirements for effective gas exchange at birth, including alignment of airways and blood vessels and lymphatic vessels. Vascular endothelial growth factors (VEGF) are potent effectors of vascular development. We examined the temporal and spatial expression of VEGF-D and specific VEGF-A isoforms at each stage of lung development. VEGF-D, expressed only by cadherin-11-positive cells of the mesenchyme, is first detected at embryonic day (E) 13.5, a period of active vasculogenesis. VEGFR-3, its cognate receptor, is detected earlier on days E11.5 to E14.5, in both blood vessels and lymphatic vessels and later, on day E17.5, in only lymphatic vessels. VEGF-A is expressed in the mesenchyme throughout lung development and also by the epithelium midway through organogenesis. Before E14, the predominant forms of VEGF-A are the soluble isoforms, VEGF-A120 and 164. Not until E14.5 do epithelial cells at the tips of expanding airways express VEGF-A, including VEGF-A188, an isoform with high affinity for extracellular matrix. Our results demonstrate unique temporal and spatial expression of VEGF-D and specific VEGF-A isoforms during lung development and suggest these related factors have distinct functions in vascular and lymphatic patterning of the lung.

Animals↗
PubMed2000

Regulation of the Hoxa4 and Hoxa5 genes in the embryonic mouse lung by retinoic acid and TGFbeta1: implications for lung development and patterning.

We have previously described a 5; cis-acting retinoic acid response element that is required for a subset of Hoxa4 expression, including the midgestation mouse lung. As both retinoids and Hox genes have been implicated in lung development and patterning, we have examined Hoxa4 expression in the developing mouse lung and extended our work on its regulation. At E12.5, a Hoxa4/lacZ transgene is expressed in the mesenchymal compartment of the lung. Later in development expression is restricted to the proximal mesenchyme and is also observed in smooth muscle cells, subepithelial fibroblasts, and alveolar cells. We show that both Hoxa4 and Hoxa5 are upregulated when cultured in the presence of all-trans retinoic acid. In addition, retinoic acid extends the domain of Hoxa4 and Hoxa5 expression to the periphery of the explants where the distal epithelia are developing. Interestingly, the effect of retinoic acid on Hoxa5 expression was not observed in a Hoxa4 mutant background. In contrast, TGFbeta1 was found to downregulate both Hoxa4 and Hoxa5 expression in cultured lung explants. We also establish that retinoic acid has the effect of proximalizing the mouse lung when cultured in a serum-free medium, as evidenced by reduced expression of the distal marker surfactant protein-C. Lungs from Hoxa4 mutant embryos exhibited a similar response to retinoic acid, suggesting that Hoxa4 alone is not required for the proximalizing effect. Based on their retinoid-dependent expression, we conclude that members of the group 4 and/or group 5 Hox genes are likely to be involved in patterning of the mouse lung. Dev Dyn 2000;217:62-74.

Animals↗
PubMedDate not supplied

Effects of intra-uterine growth restriction on the control of breathing and lung development after birth.

1. Low birthweight is now recognized as an important risk factor for early postnatal respiratory illness and it is becoming evident that low birthweight can increase the risk for airway dysfunction in children and adults. Our studies have been aimed at determining how low birthweight, resulting from intra-uterine growth restriction (IUGR), affects the control of breathing and the structural and functional development of the lung. 2. We have measured ventilatory responsiveness to progressive hypoxia and progressive hypercapnia during the first weeks after birth in postnatal lambs in which IUGR was induced by chronic placental insufficiency. It was found that the postnatal increase in ventilatory sensitivity to hypoxia observed in control lambs was diminished in low birthweight lambs; in contrast, the sensitivity to hypercapnia was not affected. In other studies, we found that IUGR caused by maternal anaemia led to elevated CO2 levels during sleep and wakefulness. 3. Our findings suggest that the prenatal development of the brain-stem or respiratory chemoreceptors may be affected by intra-uterine factors associated with IUGR, such as foetal hypoxaemia or hypoglycaemia. It is also possible that the structure of respiratory muscles and, hence, their ability to maintain a high level of ventilation may be affected by IUGR. 4. Recently, we studied the influence of IUGR on foetal lung development, in particular its effects on foetal lung liquid, a major determinant of lung growth, as well as alveolar structure and pulmonary surfactant. Lung liquid secretion and volume, in relation to bodyweight, were unaffected; however, there was evidence of structural and functional immaturity in the lungs. In foetuses exposed to IUGR, the air-blood barrier was thicker and, after birth, the diffusing capacity of the lungs for carbon monoxide was lower. In contrast, surfactant protein gene expression was enhanced, particularly in foetuses with high levels of circulating cortisol. 5. Further studies are needed to characterize the effects of specific types of prenatal compromise on postnatal control of ventilation and lung function, to determine mechanisms underlying these effects and to determine the capacity for postnatal recovery.

Animals↗
PubMed1981

A morphologic and morphometric analysis of fetal lung development in the sheep.

In the sheep, fetal lung development proceeds to a later stage of maturity than in smaller laboratory animals. Of the four stages in pulmonary development recognizable in this species - embryologic, pseudoglandular, canalicular, and aveolar - the latter three are described in the present study using histologic, morphometric, and ultrastructural techniques. During the pseudoglandular stage, the major airways developed centrifugally. Cartilaginous, glandular, muscular, vascular, and neural elements were present in major airway walls from an early age. During the canalicular stage, volume expansion of the lung was accomplished by rapid growth of large terminal spaces. In the final stage, alveoli were formed following subdivision of the large terminal spaces by alveolar crests. The alveolar lining epithelium differentiated during the latter two stages producing a large increase in alveolar surface area, particularly during the alveolar stage; a large increase in pulmonary capillary surface area also accompanied alveolar development. Thus, just prior to birth, the fetal sheep lung has a well-developed air-way system and alveolar network, in preparation for postnatal gas exchange.

Animals↗
PubMed1975

Collagen in the lung: development of a technology applicable to human lung disease.

Techniques have been developed to quantitate in vitro the types, rates and fates of collagen synthesized by animal and human lung. Studies are continuing in our laboratory to apply these techniques to investigate important lung disorders, including: (1) classification of the fibrotic lung disorders by the types of collagen synthesized; (2) development of an in vitro drug evaluation system to determine, in a lung biopsy, which drugs are useful in reducing the fibrotic process for a patient with interstitial disease; and (3) investigations of the influence of serum proteins on lung connective tissue synthesis and proteolysis.

Animals↗
PubMed2004

Epithelial-mesenchymal interactions in the developing lung.

Classical experiments in embryology have shown that normal growth, morphogenetic patterning, and cellular differentiation in the developing lung depend on interactive signaling between the endodermal epithelium and mesenchyme derived from splanchnic mesoderm. These interactions are mediated by a myriad of diffusible factors that are precisely regulated in their temporal and spatial expression. In this review we first describe factors regulating formation of the embryonic foregut. We then discuss the experiments demonstrating the importance of tissue interactions in lung patterning and differentiation. Finally, we detail the roles that a few key signaling systems-fibroblast growth factors and their receptors, sonic hedgehog and Gli genes, Wnt genes and beta-catenin, and BMP4-play as mediators of epithelial-mesenchymal interactions in the developing lung.

Animals↗
PubMed1992

Structural analysis of fetal rat lung development.

The primary aim of this morphological investigation was to elaborate a concept allowing us to coherently define reference spaces for morphometric analysis of fetal lung development. Beyond this quantitative goal, morphological analysis of cell types, definition of compartments, and reflection about the prospective fate of their constituents provided per se new insights into the developmental processes. Lungs of rat fetuses aged 17-23 days and newborns aged 20 hours were fixed with an osmium tetroxide and glutaraldehyde mixture and their volume determined. Left lungs were embedded in Epon and investigated by light and electron microscopy. The right lung of one animal per group was embedded in methacrylate and step sections obtained to precisely locate the airways within the mesenchyme. The various cell types, their topographical relationships, and their morphological alterations with ongoing development were analyzed with regard to their prospective potentials of differentiation. The developing lung could be partitioned into four zones further subdivided into defined compartments. Zone I forms a superficial mantle around the lobes and the future acini. Consisting of primitive mesenchymal cells, it represents a zone of growth which disappears with the onset of the saccular stage. Zone II is mainly a zone of differentiation. Its interstitium stains intensely due to a dense population of dark cells. Up to gestational day 19, zone II contains future conductive airways with their vessels. After day 21, it comprises the whole prospective gas exchange region. Zones III and IV contain the elements of the airway tree and vascular system, zone IV corresponding to the most proximal generations with an adventitial layer. For all differentiation processes, a centrifugal directionality is manifested.

Animals↗
PubMed2006

Structural aspects of postnatal lung development - alveolar formation and growth.

The human lung is born with a fraction of the adult complement of alveoli. The postnatal stages of human lung development comprise an alveolar stage, a stage of microvascular maturation, and very likely a stage of late alveolarization. The characteristic structural features of the alveolar stage are well known; they are very alike in human and rat lungs. The bases for alveolar formation are represented by immature inter-airspace walls with two capillary layers with a central sheet of connective tissue. Interalveolar septa are formed by folding up of one of the two capillary layers. In the alveolar stage, alveolar formation occurs rapidly and is typically very conspicuous in both species; it has therefore been termed 'bulk alveolarization'. During and after alveolarization the septa with double capillary networks are restructured to the mature form with a single network. This happens in the stage of microvascular maturation. After these steps the lung proceeds to a phase of growth during which capillary growth by intussusception plays an important role in supporting gas exchange. In view of reports that alveoli are added after the stage of microvascular maturation, the question arises whether the present concept of alveolar formation needs revision. On the basis of morphological and experimental findings we can state that mature lungs contain all the features needed for 'late alveolarization' by the classical septation process. Because of the high plasticity of the lung tissues, late alveolarization or some forms of compensatory alveolar formation may be considered for the human lung.

Animals↗