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PubMed2004

Fgf18 is required for embryonic lung alveolar development.

Fgf18 is abundantly expressed in mouse embryonic lungs. To elucidate the roles of Fgf18 in mouse embryonic lung development, we examined the Fgf18-/- embryonic lungs. Although the sizes of the Fgf18-/- lungs were a little smaller in appearance than those of wild-type lungs, neither proximal nor distal airway branching in the Fgf18-/- lungs was impaired. However, the Fgf18-/- lungs at E18.5 had reduced alveolar space, thicker interstitial mesenchymal compartments, and many embedded capillaries. Cell proliferation in the Fgf18-/- lungs was also transiently reduced around E17.5, although the expression of marker genes for lung epithelial cells in the Fgf18-/- lungs was not impaired. The present findings indicate that the Fgf18 plays roles in lung alveolar development during late embryonic lung development stages. The cell proliferation during the terminal saccular stage stimulated by Fgf18 might play roles in the remodeling of the distal lung.

Animals↗
PubMed1989

Influence of high frequency ventilation at different end-expiratory lung volumes on the development of lung damage during lung lavage in rabbits.

The effects of high frequency ventilation in combination with sustained inflations was studied in the surfactant-deficient lungs of 18 New Zealand White rabbits (weight 1.9-2.1 kg) during anaesthesia with urethane and neuromuscular block with pancuronium. Lung damage was induced by repeated lung lavage. In nine rabbits (group I) baseline ventilator settings were maintained constant throughout the study and airway pressure was readjusted to achieve a constant tidal volume. In the other nine rabbits (group II), ventilation was reinstituted after lung lavage with one period of four sustained inflations followed immediately by high frequency ventilation. In group I there was a significant decrease in gas exchange for oxygen and deterioration in pulmonary mechanics, whereas in group II there was little change in baseline blood-gas values or pulmonary mechanics. These data suggest that, with adequate ventilatory management during the period of lung lavage, the lung damage produced by this manoeuvre may be obviated.

Anesthesia, Intravenous↗
PubMed2005

Epithelial laminin alpha5 is necessary for distal epithelial cell maturation, VEGF production, and alveolization in the developing murine lung.

Laminin alpha5 is prominent in the basement membrane of alveolar walls, airways, and pleura in developing and adult lung. Targeted deletion of laminin alpha5 in mice causes developmental defects in multiple organs, but embryonic lethality has precluded examination of the latter stages of lung development. To identify roles for laminin alpha5 in lung development, we have generated an inducible lung epithelial cell-specific Lama5 null (SP-CLama5(fl/-)) mouse through use of the Cre/loxP system, the human surfactant protein C promoter, and the reverse tetracycline transactivator. SP-CLama5(fl/-) embryos exposed to doxycycline from E6.5 died a few hours after birth. Compared to control littermates, SP-CLama5(fl/-) lungs had dilated, enlarged distal airspaces, but basement membrane ultrastructure was preserved. Distal epithelial cell differentiation was perturbed, with a marked reduction of alveolar type II cells and a virtual absence of type I cells. Cell proliferation was reduced and apoptosis was increased. Capillary density was diminished, and this was associated with a decrease in total lung VEGF production. Overall, these findings indicate that epithelial laminin alpha5, independent of its structural function, is necessary for murine lung development, and suggest a role for laminin alpha5 in signaling pathways that promote alveolar epithelial cell differentiation and VEGF expression.

Animals↗
PubMed1997

Expression of glycogen phosphorylase isozymes in developing rat lung.

Glycogen accumulates to significant levels in epithelial cells of the developing respiratory tract. Mobilization of glycogen stores is regulated differentially along the respiratory epithelium such that glycogenolysis in the alveolar epithelium (the site of surfactant synthesis) precedes that in the bronchial and bronchiolar epithelium. The initial step in glycogen degradation is catalyzed by glycogen phosphorylase, which exists as three genetically distinct isozymes referred to as muscle, liver, and brain isoforms. The goal of this study was to characterize the temporal and spatial expression of each of the glycogen phosphorylase isozymes in developing lung to determine which isoform(s) was associated with glycogen mobilization in the fetal type II epithelial cell. RNA levels encoding glycogen phosphorylase were assessed by ribonuclease protection assay using isoform-specific antisense probes. RNAs encoding the brain and liver isozymes were detected in isolated day 20 fetal type II epithelial cells and at lower levels in adult type II cells. The muscle isoform RNA was barely detectable in fetal type II cells and was undetectable in adult type II cells. Expression of brain and liver isoform RNAs was higher in whole fetal lung than in fetal type II cells. Consistent with this result, in situ hybridization studies demonstrated widespread expression of the brain and liver isoforms in developing lung tissues; in contrast, expression of the muscle isoform was restricted to the pulmonary vein. Glycogen phosphorylase enzyme activity corresponding to the brain isoform was clearly detected in isolated fetal type II cells; however, the majority of enzyme activity migrated as two bands with distinct electrophoretic mobilities that may have been the result of isoform heterodimerization. Collectively, these results suggest that the brain and liver isoforms of glycogen phosphorylase may be involved in mobilization of type II cell glycogen during late fetal lung development.

Animals↗
PubMed2005

Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.

To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-ras(G12C) allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-ras(G12C) caused multiple, small lung tumors over a 12-month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well-differentiated adenomas. This is in contrast to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-ras(G12C) was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38 and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of doxycycline for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-ras(G12C) expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.

Adenoma↗
PubMed1987

The postnatal development and growth of the human lung. II. Morphology.

The morphology of postnatal human lung development and growth has been investigated by light and by scanning and transmission electron microscopy in seven children dying from non-respiratory causes and aged between 26 days and 64 months. The findings are compared with those of adult human lungs and are discussed in relation to the postnatal lung development in other species, particularly rodents. Within the first 1 1/2 postnatal years lung parenchyma undergoes a substantial structural remodeling due to bulk alveolar formation and to the restructuring of septal morphology. At one month alveolar formation appears to be well under way: The human lung is comparable then to a rat lung aged one week. In the parenchyma, numerous short and blunt tissue ridges, so-called secondary septa, subdivide the peripheral airspaces into an increasing number of still very shallow alveoli. The parenchymal septa present during and after alveolization are immature: they contain a double capillary network with a central, highly cellular sheet of connective tissue. The septal maturation sets in a few months after birth and consists of a reduction in the interstitial tissue mass and a complex process of capillary remodeling. Both alveolization and parenchymal maturation progress rapidly: by 6 months the lung has taken a big step towards maturity. By 1 1/2 years most septa show the adult structure where a single capillary network interwoven with connective tissue strands stabilizes the interalveolar wall. After the septal restructuring, lung development is considered complete, and the lung enters a period of normal growth that lasts until adulthood. From our observations we conclude that postnatal human lung development is made of two overlapping stages: (a) the alveolar stage, which starts in late fetal life and lasts to about 1-1 1/2 years, and (b) a stage of microvascular maturation, thought to extend from the first months after birth to the age of 2-3 years.

Adult↗
PubMed1977

The functional growth and development of the lung during the first year of life.

In this article much of the available data on lung volumes and mechanics in normal infants is assessed and summarized, and growth charts for the various parameters of lung function during the first year of life are presented. There is considerable evidence to show that lung development proceeds in a highly organized manner, and that strong linear relationships exist between lung volume and body size, between dynamic compliance and lung volume, and between airway conductance (the reciprocal of airway resistance) and lung volume. However, the latter relationship is affected both by the race and postconceptional age of the infant. Specific Airway conductance is higher during infancy than at any other time during life, and this gives the newborn infant certain advantages with which to counterbalance both the small size of his lungs and the fact that he is an obligatory nose breather.

Age Factors↗
PubMed2004

Overexpression of lunatic fringe does not affect epithelial cell differentiation in the developing mouse lung.

The Notch/Notch-ligand pathway regulates cell fate decisions and patterning in various tissues. Several of its components are expressed in the developing lung, suggesting that this pathway is important for airway cellular patterning. Fringe proteins, which modulate Notch signaling, are crucial for defining morphogenic borders in several organs. Their role in controlling cellular differentiation along anterior-posterior axis of the airways is unknown. Herein, we report the temporal-spatial expression patterns of Lunatic fringe (Lfng) and Notch-regulated basic helix-loop-helix factors, Hes1 and Mash-1, during murine lung development. Lfng was only expressed during early development in epithelial cells lining the larger airways. Those epithelial cells also expressed Hes1, but at later gestation Hes1 expression was confined to epithelium lining the terminal bronchioles. Mash-1 displayed a very characteristic expression pattern. It followed neural crest migration in the early lung, whereas at later stages Mash-1 was expressed in lung neuroendocrine cells. To clarify whether Lfng influences airway cell differentiation, Lfng was overexpressed in distal epithelial cells of the developing mouse lung. Overexpression of Lfng did not affect spatial or temporal expression of Hes1 and Mash-1. Neuroendocrine CGRP and protein gene product 9.5 expression was not altered by Lfng overexpression. Expression of proximal ciliated (beta-tubulin IV), nonciliated (CCSP), and distal epithelial cell (SP-C, T1alpha) markers also was not influenced by Lfng excess. Overexpression of Lfng had no effect on mesenchymal cell marker (alpha-sma, vWF, PECAM-1) expression. Collectively, the data suggest that Lunatic fringe does not play a significant role in determining cell fate in fetal airway epithelium.

Animals↗
PubMed1996

PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.

A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis.

Actins↗
PubMed1983

Development of terminal buds in the fetal mouse lung.

Development of the lungs in mammals begins with the formation of pharyngeal buds that undergo repeated branching to establish the bronchial tree. Late in fetal life the most superficial buds begin to form side branches that will develop into the respiratory surfaces of the lung; the alveolar ducts, alveolar sacs, and alveoli. The bronchial ciliated cells and Clara cells first appear on the seventeenth day of gestation in the mouse. In the respiratory region, a few lamellar bodies are found by 16 days but identifiable type II pneumocytes and extracellular surfactant are not found until 18 days. Flattened type I pneumocytes do not form until after birth, on day 19 or 20. The epithelial branches of the lung are surrounded by mesenchyme and covered by a capsule. At 16 days, the branches are separated by a compact mesenchyme that is highly cellular. By 18 days, the mesenchymal space begins to be reduced. By 19 days, the air passages expand and the mesenchyme forms a thin layer between branches. Little experimental work has been done on the role of the mesenchyme in differentiation of the respiratory surfaces. Since branching of the embryonic lung is influenced by the kind of mesenchyme surrounding the epithelium at early stages, it is likely that mesenchymal control is exerted at later stages in the fetus.

Animals↗
PubMed1991

Fine structural aspects of postnatal development of feline lung.

Lung development was studied in late prenatal, 1-, 7-, 14-, and 21-days postnatal and adult cats. Cats were born with a few alveoli, and the lungs appeared to have patches of primitive air spaces (saccules). The saccules of prenatal kittens were thick walled, very cellular, and lined by type II pneumocytes. Eosinophils were observed in the septum, intraepithelially, and in the alveolar space of growing cats. Secondary septa were flanked by a double capillary network and divided saccules into multiple shallow alveoli. Septation was irregular and time dependent and not completed by day 231 of postnatal life. Elastic fibers accumulated at the tip of the septa, seemingly playing an important role in alveolar formation. Type II pneumocytes were located at the base of the secondary septa in growing cats, thus strengthening secondary septa to withstand the stresses of respiration. Pores of Kohn were not observed in growing cats.

Animals↗
PubMed2000

Functional residual capacity and static compliance during the first year in preterm infants treated with surfactant.

Individual lung development during the first year of life was studied in surfactant treated preterm infants with respiratory distress syndrome (RDS) and healthy controls, as well as in a group who subsequently developed chronic lung disease of the newborn (CLDN). Lung development was assessed from functional residual capacity (FRC) and compliance of the respiratory system (Crs). Twenty-one infants with RDS after preterm birth received surfactant treatment. Six of them developed CLDN. Eighteen preterm infants without RDS served as a control group. Lung function measurements were performed at term age and 4, 8, and 12 months afterwards. FRC was obtained by means of the closed-system helium dilution technique whereas static Crs was obtained by means of the weighted spirometer technique. At term age, FRC was lower in the CLDN group compared with uncomplicated RDS and controls (p < 0.05). No significant differences between groups were found in the development of FRC during the first year of life (p = 0.4). No differences were found in Crs during the first year of life in surfactant treated infants who recovered from uncomplicated RDS and the control group. However, lower values were found in the CLDN group (p < 0.05). We conclude that surfactant treated infants without CLDN have similar lung development during the first year of life as control preterm infants.

Functional Residual Capacity↗
PubMed1995

The effect of activated alveolar macrophages on experimental lung emphysema development. III. Morphological analysis of the lung tissue and alveolar macrophages in situ.

Morphological (in light and transmission electron microscope) as well as morphometrical analysis of the lungs was performed on experimental, papain-induced lung emphysema. Development of emphysematous changes was studied seven days after a single intratracheal instillation of papain solution. The effect of alveolar macrophages (AM) activation by BCG-vaccine on changes in pulmonary tissue was analyzed. In the rats given BCG the number of AM increased and demonstrated enhanced activity. Increase in reticulin fibre density in places of AM cumulation, particularly in BCG+papain-treated rats was observed. The lungs of animals treated with BCG+papain showed enhancing of emphysema comparing with the papain-treated rats. Development of emphysematous changes, especially in BCG+papain-treated rats coexisted with cumulation of activated alveolar macrophages and collagen fibres as well as type II alveolar epithelial cells proliferation. Our data support the inflammatory-repair hypothesis of emphysema pathogenesis and indicate that AM regulate collagen production in the lung. Type II alveolar epithelial cells seem be important in lung injury and repair.

Animals↗
PubMed2001

Immunohistochemical mapping of endothelin in the developing and adult mouse lung.

Endothelins (ET) are a family of regulatory peptides displaying, among other abilities, potent constrictor actions. We studied the perinatal time course expression and distribution of ET in the mouse airway epithelium. In fetal mouse, ET-immunoreactivity (IR) appeared earlier (gestational Day 18) in the epithelium of upper (bronchi and large bronchioles) than in lower airways, being scarce and mainly located in the apical cytoplasm. As the lung developed, ET-IR became gradually stronger and extended throughout the cell in both bronchi and bronchioles. ET-IR was found in most airway epithelial cells. Clara cells were positive for ET, whereas ciliated and endocrine cells were not. In adult lungs, part of the myocytes and parenchymal cells also showed ET-IR. In both developing and adult mouse lungs, the cell distribution of ET-IR in the epithelium is compatible with apical and/or basal secretion. The presence of ET in mouse airway epithelium during the perinatal period may indicate a role for ET as a growth factor in lung development and its involvement in control of lung ventilation at birth.

Animals↗
PubMed1998

Ultrastructural studies on selected elements of the extracellular matrix in the developing rat lung alveolus.

As the respiratory system adapts to the extrauterine life, the extracellular matrix (ECM) plays an important structural and regulatory role during its development. Therefore the purpose of this investigation was to analyze ultrastructurally several elements of extracellular connective tissue during the process of rat lung development. Morphological observations were mainly focused on the terminal part of respiratory system. To outline different components of connective tissue network, several ultrastructural techniques were used (both histochemical and immunohistochemical). The distribution and amount of the following proteins were studied: laminin, collagen type IV, collagen fibrils (CFs), elastic fibers (EFs) and fibronectin (FN). Additionally localization of glycosaminoglycans (GAGs) was examined. The present study deals with four periods of lung development: pseudoglandular, canalicular, saccular and alveolar. In all these stages localization and amount of ECM components change rapidly. In early periods of lung development, the amount of connective tissue fibers was low, basement membranes (BMs) were incomplete, and FN was distributed nearly uniformly. Later when the process of lung alveoli formation begins, the number and thickness of both CFs and EFs rapidly increased, BMs became complete, the content and distribution of FN were irregular. In all stages of lung development GAGs were distributed in BMs and among connective tissue fibers. The results described in the present study summarize morphologically ECM changes occurring during formation of lung alveolus.

Animals↗
PubMed2001

Does the developing liver inhibit early lung growth in congenital diaphragmatic hernia?

It has been hypothesised that the liver induces lung hypoplasia in congenital diaphragmatic hernia (CDH) by non-compressive intrathoracic growth rather than traditional mass herniation. Utilising a co-culture system, we tested the capacity of liver cells to inhibit lung growth by contact rather than compression. Heart, liver, and lungs were microdissected from normal rat embryos (n > 20 from at least three litters) on day 13.5 of gestation. Monolayer cultures of enzymatically dispersed livers and hearts were established at the same cell density. Lung primordia were cultured in direct contact with hepatic cells or partitioned from them by a permeable polytetrafluoroethylene membrane. This permits the contributions of diffusable factors and cell contact to be distinguished. Lungs were similarly cultured in direct contact with or partitioned from cardiac cells. Lungs cultured in isolation served as further controls. Daily inspection permitted assessment of in-vitro lung growth. Growth of lungs in direct contact with hepatic cells was equivalent to that of lungs partitioned from liver cells. Lungs in direct contact with cardiac cells and lungs partitioned from cardiac cells were also not inhibited compared to lungs cultured in isolation. Early lung development is thus not inhibited by humoral or contact-mediated interactions with embryonic liver cells. Lung hypoplasia in CDH is therefore unlikely to originate from contact inhibition with the developing liver. An intrinsic pulmonary defect may better explain hypoplastic lung development in CDH.

Animals↗
PubMed2006

NPAS1 regulates branching morphogenesis in embryonic lung.

Drosophila trachealess (Trl), master regulator of tracheogenesis, has no known functional mammalian homolog. We hypothesized that genes similar to trachealess regulate lung development. Quantitative (Q)RT-PCR and immunostaining were used to determine spatial and temporal patterns of npas1 gene expression in developing murine lung. Immunostaining for alpha-smooth muscle actin demonstrated myofibroblasts, and protein gene product (PGP)9.5 identified neuroendocrine cells. Branching morphogenesis of embryonic lung buds was analyzed in the presence of antisense or sense oligodeoxynucleotides (ODN). Microarray analyses were performed to screen for changes in gene expression in antisense-treated lungs. QRT-PCR was used to validate the altered expression of key genes identified on the microarrays. We demonstrate that npas1 is expressed in murine embryonic lung. npas1 mRNA peaks early at Embryonic Day (E)10.5-E11.5, then drops to low levels. Sequencing verifies the identity of npas1 transcripts in embryonic lung. NPAS1 immunostaining occurs in nuclei of parabronchial mesenchymal cells, especially at the tracheal bifurcation. Arnt, the murine homolog of Tango (the heterodimerization partner for Trl) is also expressed in developing lung but at constant levels. npas1- or arnt-antisense ODN inhibit lung branching morphogenesis, with altered myofibroblast development and increased pulmonary neuroendocrine cells. On microarrays, we identify > 50 known genes down-regulated by npas1-antisense, including multiple genes regulating cell migration and cell differentiation. QRT-PCR confirms significantly decreased expression of the neurogenic genes RBP-Jk and Tle, and three genes involved in muscle development: beta-ig-h3, claudin-11, and myocardin. Npas1 can regulate myofibroblast distribution, branching morphogenesis, and neuroendocrine cell differentiation in murine embryonic lung.

Animals↗
PubMed2006

Hyperoxia and apoptosis in developing mouse lung mesenchyme.

Hyperoxia contributes to the development of bronchopulmonary dysplasia in former premature infants. Injurious environmental factors such as hyperoxia may disrupt distal airway branching and alveolar septation, as these critical stages in lung development occur following birth in extremely premature infants. To test if hyperoxia directly inhibited distal airway branching, we cultured E16 fetal mouse lung explants in either 20% (control) or 95% oxygen (hyperoxia). Hyperoxia reduced the number of distal airways to less than 50% of controls. Explants cultured in 95% oxygen also had fewer complex distal airways compared with controls. Mesenchymal cells adjacent to distal airways in hyperoxic explants appeared apoptotic by phase microscopy. Consistent with increased apoptosis, explants cultured in hyperoxia had increased caspase 3/7 activity compared with controls. Hyperoxia also increased mesenchymal caspase 3 expression and annexin V binding within cultured explants as visualized by fluorescence microscopy. We measured increased annexin V binding in isolated primary fetal lung mesenchymal cells cultured in 95% oxygen suggesting a direct effect on cells within the mesenchyme. Hyperoxia can lead to NF-kappaB activation, which mediates inflammatory cascades and may protect cells from apoptosis. We detected NF-kappaB activation and nuclear p65 localization in explants exposed to 48 h of hyperoxia. Inhibition of NF-kappaB prevented the hyperoxia-induced activation of caspase 3. NF-kappaB activation may therefore contribute to apoptosis in the developing fetal mouse lung following hyperoxia exposure. Our data suggest hyperoxia inhibits distal airway branching and directly induces apoptosis of the fetal mouse lung mesenchyme.

Animals↗