Lung development and fetal lung growth.
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Biomechanical Phenomena↗
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Redox regulation of lung development and perinatal lung epithelial function.
Throughout gestation, low oxygen tensions are a dominant feature of the fetal environment and so may be important in sustaining a normal pattern of lung morphogenesis until the moment of birth. As breathing begins, the equilibration of the lung lumen to postnatal PO2 evokes a series of physiologic and morphogenic maturation events that are partially reversible by hypoxia. In this review, we discuss the experimental evidence that fetal and perinatal oxygen tensions differently influence lung morphogenesis through oxygen- and redox-responsive signaling pathways and identify five loci at which this regulation may occur: (I) proliferation of undifferentiated lung mesenchyme as governed by hypoxia-regulated transcription factors (HIF-1alpha, C/EBPbeta); (II) transient production of reactive oxygen species (ROS) and nuclear oxidation of the perinatal lung epithelium; (III) nuclear transport and oxidation of thioredoxin in hand with the acute activation of nuclear factor- kappaB (NF-kappaB); (IV) ROS-evoked chronic rise in intracellular glutathione and thioredoxin redox buffering capacity; and (V) NF-kappaB-dependent increase in transepithelial Na+ transport and lung lumenal fluid clearance. Although not exhaustive, this analysis leads us to the conclusion that redox events that occur in the lung during gestation, parturition, and the early neonatal period may dramatically influence the expression of genes and physiological events that are crucial to the successful transition from fetal to postnatal lung maturation.
Animals↗
Role of cytokines in hyperoxia mediated inflammation in the developing lung.
The development of Chronic Lung Disease of Prematurity (CLD) has been associated with the use of hyperoxic conditions during ventilation. Inflammation has been demonstrated to contribute to the development of this disease, both on histological examination of diseased lungs, and by the use of bronchoalveolar lavage. Hyperoxia is believed to contribute to this inflammatory process by causing direct injury to epithelial and endothelial cells. The formation of reactive oxygen species is thought to result in production of cytokines. These act within a complex network, orchestrating an inflammatory response. Evidence for a role of cytokines in CLD has been inferred by studies in human infants showing increased concentrations of cytokines, growth factors and inflammatory cells at early stages in infants destined to develop CLD. These findings have been supported by the use of animal models of hyperoxic lung injury. The treatment of CLD is currently centered on the suppression of cytokine production. As understanding of this disease increases, more specific targets are being developed which aim to reduce the oxidative load on the lung, and prevent recruitment of inflammatory cells that are responsible for the tissue damage underlying this disease.
Animals↗
Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development.
PDGF-A(-/-) mice lack lung alveolar smooth muscle cells (SMC), exhibit reduced deposition of elastin fibres in the lung parenchyma, and develop lung emphysema due to complete failure of alveogenesis. We have mapped the expression of PDGF-A, PDGF receptor-alpha, tropoelastin, smooth muscle alpha-actin and desmin in developing lungs from wild type and PDGF-A(-/-) mice of pre- and postnatal ages in order to get insight into the mechanisms of PDGF-A-induced alveolar SMC formation and elastin deposition. PDGF-A was expressed by developing lung epithelium. Clusters of PDGF-Ralpha-positive (PDGF-Ralpha+) mesenchymal cells occurred at the distal epithelial branches until embryonic day (E) 15.5. Between E16.5 and E17.5, PDGF-Ralpha+ cells multiplied and spread to acquire positions as solitary cells in the terminal sac walls, where they remained until the onset of alveogenesis. In PDGF-A(-/-) lungs PDGF-Ralpha+ cells failed to multiply and spread and instead remained in prospective bronchiolar walls. Three phases of tropoelastin expression were seen in the developing lung, each phase characterized by a distinct pattern of expression. The third phase, tropoelastin expression by developing alveolar SMC in conjunction with alveogenesis, was specifically and completely absent in PDGF-A(-/-) lungs. We propose that lung PDGF-Ralpha+ cells are progenitors of the tropoelastin-positive alveolar SMC. We also propose that postnatal alveogenesis failure in PDGF-A(-/-) mice is due to a prenatal block in the distal spreading of PDGF-Ralpha+ cells along the tubular lung epithelium during the canalicular stage of lung development.
Animals↗
Retinoic acid stimulates mouse lung development by a mechanism involving epithelial-mesenchymal interaction and regulation of epidermal growth factor receptors.
Retinoic acid (RA) stimulated proliferation of both epithelial and mesenchymal cells in cocultures isolated from developing mouse lungs. There was a corresponding increase in epithelial branching activity in organ culture of embryonic lungs exposed to similar doses of RA. Stimulation was maximal with concentrations of 1 microM and progressively decreased with either lower or higher concentrations. However, when lung cell monocultures of isolated epithelial and mesenchymal cells were exposed to RA, the mitogenic effect was observed only in the mesenchymal population. This suggests that RA may not have a direct mitogenic effect on epithelial cells but rather functions indirectly through the mesenchyme. The cellular response to RA was correlated with an increase in the expression of epidermal growth factor receptor (EGFR). Epidermal growth factor (EGF) also stimulated terminal branch formation in the developing lung. Unlike RA, EGF stimulated proliferation in both epithelial cells and mesenchymal cells in monoculture. In comparison, transforming growth factor-alpha, which also binds to the EGFR, elicited no response. We conclude that RA stimulates cell proliferation and branching activity in the developing mouse lung by a mechanism involving epithelial-mesenchymal interactions. The effect is, in part, produced by stimulation of EGFR expression, with the resulting amplification of the cellular response to EGF or other EGFR ligands. In this process the mesenchyme provides a paracrine support to the epithelium, otherwise unresponsive to RA. Further studies identified the mesenchyme as a major source of EGF in the embryonic lung, suggesting that mesenchymal EGF may represent a paracrine factor involved in the epithelial response to RA.
Animals↗
Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia.
Hyperoxia disrupts vascular and alveolar growth of the developing lung and contributes to the development of bronchopulmonary dysplasia (BPD). Endothelial progenitor cells (EPC) have been implicated in repair of the vasculature, but their role in lung vascular development is unknown. Since disruption of vascular growth impairs lung structure, we hypothesized that neonatal hyperoxia impairs EPC mobilization and homing to the lung, contributing to abnormalities in lung structure. Neonatal mice (1-day-old) were exposed to 80% O(2) at Denver's altitude (= 65% at sea level) or room air for 10 days. Adult mice were also exposed for comparison. Blood, lung, and bone marrow were harvested after hyperoxia. Hyperoxia decreased pulmonary vascular density by 72% in neonatal but not adult mice. In contrast to the adult, hyperoxia simplified distal lung structure neonatal mice. Moderate hyperoxia reduced EPCs (CD45-/Sca-1+/CD133+/VEGFR-2+) in the blood (55%; P < 0.03), bone marrow (48%; P < 0.01), and lungs (66%; P < 0.01) of neonatal mice. EPCs increased in bone marrow (2.5-fold; P < 0.01) and lungs (2-fold; P < 0.03) of hyperoxia-exposed adult mice. VEGF, nitric oxide (NO), and erythropoietin (Epo) contribute to mobilization and homing of EPCs. Lung VEGF, VEGF receptor-2, endothelial NO synthase, and Epo receptor expression were reduced by hyperoxia in neonatal but not adult mice. We conclude that moderate hyperoxia decreases vessel density, impairs lung structure, and reduces EPCs in the circulation, bone marrow, and lung of neonatal mice but increases EPCs in adults. This developmental difference may contribute to the increased susceptibility of the developing lung to hyperoxia and may contribute to impaired lung vascular and alveolar growth in BPD.
Aging↗
The role of apoptosis in normal and accelerated lung development in fetal rabbits.
BACKGROUND/PURPOSE: During fetal development, the mammalian lung undergoes progressive parenchymal involution. Intrauterine tracheal occlusion induces accelerated architectural maturation of the fetal lungs associated with depletion of the surfactant-producing type II cells. This study investigates the spatiotemporal pattern of apoptosis during normal fetal lung development and its modulation in tracheal occlusion-induced accelerated fetal lung growth. METHODS: Fetal rabbit lungs were studied at 25 to 31 days' gestational age (DGA; term, 31 DGA), corresponding to late pseudoglandular through terminal air sac stages of fetal lung development. Intrauterine tracheal ligation (TL) was performed at 24 DGA. TL fetuses were monitored until 29 DGA, a time-point previously shown to coincide with significant type II cell depletion. Apoptotic cells were identified by light and electron microscopy, as well as terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick-end labeling (TUNEL). Epithelial (type I and II) cell apoptosis was studied by TUNEL labeling in conjunction with antisurfactant protein and anticytokeratin immunohistochemistry. DNA fragmentation was analyzed by gel electrophoresis. Sham-operated littermates served as controls. RESULTS: The number of apoptotic cells progressively increased with advancing lung growth and architectural maturation (apoptotic index [Al] 1.2 +/- 0.7 x 10(-3) at 25 DGA v 4.2 +/- 1.4 x 10(-3) at 31 DGA; P< .05, analysis of variance). In TL fetuses, the apoptotic rate was significantly higher than in non-TL fetuses from the third postligation day on, coinciding with the onset of significantly increased airspace distension (Al 4.9 +/- 1.3 x 10(-3) in TL v2.6 +/- 0.4 x 10(-3) in controls at 29 DGA; P< .05, Student's ttest). Apoptosis occurred in parenchymal cells and in isolated cells within the airspaces. The apoptotic activity of type II cells was significantly higher in TL fetuses than C fetuses at 29 DGA (type II Al 25.5 +/- 6.3 x 10(-3) in TL v2.3 +/- 0.8 x 10(-3) in C; P< .001). Electron microscopic studies confirmed the presence of apoptotic nuclei in interstitial macrophages and in degenerating intraluminal type II cells. DNA analysis showed nucleosomal bands. CONCLUSIONS: Normal fetal lung development is associated with a progressive increase of epithelial and interstitial apoptotic activity, a process enhanced by TL. Tracheal occlusion induces a significant increase of type II cell apoptosis, which likely contributes to the observed type II cell depletion after TL. We speculate that fetal type II cell apoptosis after TL may be induced by mechanical distension (stretch) of the airspaces.
Animals↗
Brain-associated small-cell lung cancer antigen (BASCA) is expressed in developing lung: an immunohistochemical and immunoelectron microscopic study.
Expression of brain-associated small-cell lung cancer antigen (BASCA) in developing lung and in lung tumors was investigated immunohistochemically and immunoelectron microscopically with monoclonal antibodies recognizing different epitopes of BASCA. In fetal lung, epithelial and mesenchymal cells had different spatial and temporal expression patterns, in contrast to the consistent pattern in neural cells. The cell membranes of epithelial cells of the proximal bronchial tubes were diffusely positive at the pseudoglandular stage. Ciliated cells lost immunoreactivity shortly after their emergence, but non-ciliated cells, including endocrine cells, lost it at the alveolar stage. The immunoreactivity in mesenchymal cells was reduced in the proximal airway, but positivity remained in the distal lung later during the postnatal period. All endocrine tumors of the lung, defined by diffuse synaptophysin immunoreactivity, expressed BASCA, but some non-endocrine carcinomas which also lacked densely cored granules ultrastructurally, showed BASCA positivity. The temporal and spatial pattern of BASCA expression in the developing lung suggests that BASCA plays an active role in lung morphogenesis. BASCA may be expressed as an oncofetal substance in some non-endocrine carcinomas of the lung.
Adult↗
Lung development in laminin gamma2 deficiency: abnormal tracheal hemidesmosomes with normal branching morphogenesis and epithelial differentiation.
BACKGROUND: Laminin gamma2 (Lamc2), one of the polypeptides in laminin-332 (laminin-5), is prominent in the basement membrane of alveolar walls and airways of developing and adult lung. Laminins are important for lung morphogenesis and based on its localization, a function for laminin gamma2 in lung development has been hypothesized. Targeted deletion of the laminin gamma2 gene in mice results in skin blistering and neonatal death at 3-5 days after birth due to failure to thrive. METHODS: Examination of lung development in Lamc2-/- mice through 1-2 days postnatal was accomplished by morphometric analysis, lung bud culture, electron microscopy, immunohistochemical and immunofluorescence staining. RESULTS: Compared to littermate controls, Lamc2-/- lungs were similar in morphology during embryonic life. At post-natal day 1-2, distal saccules were mildly dilated by chord length measurements. Epithelial differentiation as evaluated by immunohistochemical staining for markers of ciliated cells, Clara cells, alveolar type I cells and alveolar type II cells did not reveal a difference between Lamc2-/- and littermate control lungs. Likewise, vascular development, smooth muscle cell differentiation, and elastic fiber formation looked similar, as did airway basement membrane ultrastructure. Branching morphogenesis by lung bud culture was similar in Lamc2-/- and littermate control lungs. Since laminin-332 is important for hemidesmosome formation, we examined the structure of tracheal hemidesmosomes by transmission electron microscopy. Compared to littermate controls, Lamc2-/- tracheal hemidesmosomes were less organized and lacked the increased electron density associated with the basement membrane abutting the hemidesmosome. CONCLUSION: These findings indicate that laminin gamma2 and laminin-332, despite their prominence in the lung, have a minimal role in lung development through the saccular stage.
Animals↗
Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development.
Recent reports have demostrated a link between expression of members of the family of heterogeneous nuclear ribonucleoproteins (hnRNPs) and cancer. Overexpression of hnRNP A2/B1 correlated with the eventual development of lung cancer in three different clinical cohorts. We have studied the expression of hnRNP A2/B1 messenger RNA (mRNA) and protein during mammalian development. The expression of hnRNP A2/B1 mRNA and protein are parallel but change dynamically during critical periods in mouse pulmonary development. hnRNP A2/B1 is first detected in the lung in the early pseudoglandular period, peaks at the beginning of the canalicular period, and remains high during the saccular (alveolar) period. In mouse and rat, hnRNP A2/B1 expression is first evident in the earliest lung buds. As lung development progresses, the cuboidal epithelial cells of the distal primitive alveoli show high levels of the ribonucleoprotein, which is almost undetectable in the proximal conducting airways. The expression of hnRNP A2/ B1 is restricted in mature lung. Similar dynamic pattern of expression through lung development was also found in rat and human lung. Upregulated expression of hnRNP A2/B1 at critical periods of lung development was comparable to the level of expression found in lung cancers and preneoplastic lesions and is consistent with hnRNP A2/B1 overexpression playing an oncodevelopmental role.
Animals↗
Spatial and temporal distribution of nerves, ganglia, and smooth muscle during the early pseudoglandular stage of fetal mouse lung development.
Neural tissue and smooth muscle appear early in the developing fetal lung, but little is known of their origin and subsequent distribution. To investigate the spatial and temporal distribution of nerves, ganglia, and airway smooth muscle during the early pseudoglandular stage, fetal mouse lungs at embryonic days (E) 11 to 14 were immunostained as whole-mounts and imaged by confocal microscopy. At E11, the primordial lung consisted of the future trachea and two budding epithelial tubules that were covered in smooth muscle to the base of the growing buds. The vagus and processes entering the lung were positive for the neural markers PGP 9.5 (protein gene product 9.5) and synapsin but no neurons were stained at this stage. An antibody to p75NTR revealed neural crest cells on the future trachea as well as in the vagus and in processes extending from the vagus to the lung. This finding indicates that even though neuronal precursors are already present at this stage, they are still migrating into the lung. By E12, neural tissue was abundant in the proximal part of the lung and nerves followed the smooth muscle-covered tubules to the base of the growing buds. At E13 and E14, a neural network of interconnected ganglia, innervated by the vagus, covered the trachea. The postganglionic nerves mainly followed the smooth muscle-covered tubules, but some extended out into the mesenchyme beyond the epithelial buds. Furthermore, we show in a model of cultured lung explants that neural tissue and smooth muscle persist and continue to grow and differentiate in vitro. By using fluorescent markers and confocal microscopy, we present the developing lung as a dynamic structure with smooth muscle and neural tissue in a prime position to influence growth and development.
Actins↗
Transcriptional regulation of lung development: emergence of specificity.
The lung is the product of a set of complex developmental interactions between two distinct tissues, the endodermally derived epithelium and the mesoderm. Each tissue contributes to lung development by fine-tuning the spatial and temporal pattern of gene expression for a distinct array of signaling molecules, transcriptional molecules and molecules related to the extracellular matrix. Morphoregulatory transcriptional factors such as NKX2.1 have the crucial role of connecting the cell-cell crosstalk to the activation or repression of gene expression through which processes such as cellular proliferation, migration, differentiation and apoptosis can be controlled. Although none of the factors participating in lung development are exclusively lung-specific, their unique combinations and interactions constitute the basis for emergence of lung structural and functional specificities. An understanding of the individual molecules and their unique interactions in the context of lung development is necessary for the construction of a morphogenetic map for this vital organ as well as for the development of rational and innovative approaches to congenital and induced lung disease.
Animals↗
The role of vascular growth factors in hyperoxia-induced injury to the developing lung.
Normal pulmonary vascular development is the result of a complex interplay of growth factors, including vascular endothelial growth factor (VEGF) and the angiopoietins. Injury to the developing lung, whether due to hyperoxia or mechanical ventilation, results in disordered vascular development, ranging from an apparent arrest of microvascular development in milder injury to extensive microvascular derangement in more severe injury. Alterations in vascular growth factors may participate in these injuries. During injury to the developing animal lung, VEGF abundance is markedly decreased. In models of post-injury recovery, up-regulation of VEGF accompanies the re-establishment of normal vasculature. Alterations in lung VEGF levels in human premature infants are less clear cut. However, among humans premature newborns who later go on to develop bronchopulmonary dysplasia (BPD), VEGF production is decreased in comparison to those newborns who recover. Other angiogenic factors, such as the CXC ELR+ chemokines, are also altered in injury to the developing lung, but their specific roles in vascular injury are less clear. Strategies that enhance microvascular integrity, whether through attenuating alterations in vascular growth factors or by other means, also improve the outcome of lung injury. Such therapies may eventually offer hope in human BPD.
Angiogenesis Inducing Agents↗
Extracellular matrix and the regulation of lung development and repair.
During lung development the extracellular matrix regulates cellular growth, migration, and differentiation. Pulmonary cells reciprocate and regulate extracellular matrix formation by elaborating a variety of peptides that affect gene transcription, RNA processing, translation, and posttranslational modifications of proteins. This regulation involves prenatal events such as the branching of airways and postnatal events such as alveolar septal formation. Normal airway branching requires multiple extracellular matrix proteins, proteoglycans, and the expression of cellular receptors for these molecules. Alveolar septal formation exemplifies how cells regulate the production, export, and deposition of an important structural protein, elastin, which is essential for the development of normal gas exchange units. Repair after injury to the adult lung engages some of the same factors that regulate lung development. However, in this case, inflammatory cells that enter the lung after injury elaborate many of these regulatory peptides. The effects of these peptides on the resident cells, which produce extracellular matrix, are a major determinant of whether the repair restores normal pulmonary architecture or progresses to fibrosis and additional impairment of gas exchange.
Animals↗
Lung development and susceptibility to ventilator-induced lung injury.
RATIONALE: Ventilator-induced lung injury has been predominantly studied in adults. OBJECTIVES: To explore the effects of age and lung development on susceptibility to such injury. METHODS: Ex vivo isolated nonperfused rat lungs (infant, juvenile, and adult) were mechanically ventilated where VT was based on milliliters per kilogram of body weight or as a percentage of the measured total lung capacity (TLC). In vivo anesthetized rats (infant, adult) were mechanically ventilated with pressure-limited VTs. Allocation to ventilation strategy was randomized. MEASUREMENTS: Ex vivo injury was assessed by pressure-volume analysis, reduction in TLC, and histology, and in vivo injury by lung compliance, cytokine production, and wet- to dry-weight ratio. MAIN RESULTS: Ex vivo ventilation (VT 30 ml.kg(-1)) resulted in a significant reduction (36.0 +/- 10.1%, p < 0.05) in TLC in adult but not in infant lungs. Ex vivo ventilation (VT 50% TLC) resulted in a significant reduction in TLC in both adult (27.8 +/- 2.8%) and infant (10.6 +/- 7.0%) lungs, but more so in the adult lungs (p < 0.05); these changes were paralleled by histology and pressure-volume characteristics. After high stretch in vivo ventilation, adult but not infant rats developed lung injury (total lung compliance, wet/dry ratio, tumor necrosis factor alpha). Surface video microscopy demonstrated greater heterogeneity of alveolar distension in ex vivo adult versus infant lungs. CONCLUSION: These data provide ex vivo and in vivo evidence that comparable ventilator settings are significantly more injurious in the adult than infant rat lung, probably reflecting differences in intrinsic susceptibility or inflation pattern.
Animals↗
The molecular basis for abnormal human lung development.
Our understanding of lung development in the past two decades has moved from an anatomical to a histological basis and, most recently, to a molecular basis. Tissue interactions specify tracheal and lung primordia formation, program branching morphogenesis of the airway epithelium and regulate epithelial differentiation. In addition, lung development is influenced by mechanical and humoral factors. The regulatory molecules involved in morphogenetic signaling include growth and transcription factors and extracellular matrix molecules. These morphogenetic signals are responsible for lung patterning and differentiation. We will provide a brief overview of molecular signaling during early respiratory formation, airway branching, pulmonary vascularization and epithelial differentiation. We will then review aberrant morphogenetic signaling in human lung abnormalities, such as tracheoesophageal fistula, congenital diaphragmatic hernia, pulmonary hyperplasia, alveolar capillary dysplasia, congenital cystic adenomatoid malformation and bronchopulmonary dysplasia.
Aging↗
Synthesis and expression of laminin during human foetal lung development.
BACKGROUND: The lung develops by epithelial tubes budding and branching into a flexible mesenchyme. This growth is associated with the remodelling of the epithelial basement membrane, of which laminin is a major component. METHODS: Both the synthesis and expression of laminin were studied in the human lung between 10 and 31 weeks of gestation, using in situ hybridization and immunohistochemistry. RESULTS: The synthesis of the beta chain was active in the epithelial and surrounding mesenchymal cells. The mRNAs coding for the gamma chain were less abundant and mainly found in the epithelium. The synthesis of these two chains continued throughout gestation, and no significant difference in the density of hybridization grains could be detected between the tips of the expanding buds and the proximal portions. Immunohistochemical localization of laminin showed important modifications of the basement membrane during gestation. In the first part of the pseudoglandular stage the epithelial basement membrane stained continuously for laminin. Later, the basement membrane was labelled in a graded fashion: at the apex of the growing buds the staining became weak with focal disruptions. Both epithelial and mesenchymal synthesis of laminin remained active, while the polypeptide was undetectable using immunohistochemistry. CONCLUSIONS: These findings suggest that the remodelling of the basement membrane during human lung morphogenesis is probably not related to a decreasing synthesis of laminin, but to either a proteolytic degradation or the assembly of an inadequate complex undetectable with the polyclonal antibody antilaminin.
Embryonic and Fetal Development↗
Transcription factors and pattern formation in the developing lung.
During development of the respiratory tract embryonic cells are instructed to organize themselves along an axis and differentiate, such that proximal structures (trachea) greatly differ from those in distal alveoli. Pattern formation relates to this process of organization, and it is believed to be transcriptionally regulated in many developmental systems. Although the lung is the site of expression of many transcription factors, such as Hox, retinoid receptors, hepatocyte nuclear factors, and myc, among others, little information is available on how they influence lung pattern. Functional studies so far have directly implicated the product of the protooncogene N-myc and the retinoic acid receptors as transcriptional regulators of lung patterning, and it is likely that tissue-specific homeobox genes, such as the thyroid transcription factor-1, play an important role in distal lung formation. This review describes several aspects of transcription factors possibly involved in lung patterning, including structure, spatial distribution, and their putative functions.
Aging↗