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At least 145 records · Page 8Linked to original sources
PubMed2004

Functional diversity of notch family genes in fetal lung development.

In Drosophila, developmental signaling via the transmembrane Notch receptor modulates branching morphogenesis and neuronal differentiation. To determine whether the notch gene family can regulate mammalian organogenesis, including neuroendocrine cell differentiation, we evaluated developing murine lung. After demonstrating gene expression for notch-1, notch-2, notch-3, and the Notch ligands jagged-1 and jagged-2 in embryonic mouse lung, we tested whether altering expression of these genes can modulate branching morphogenesis. Branching of embryonic day (E) 11.5 lung buds increased when they were treated with notch-1 antisense oligodeoxynucleotides in culture compared with the corresponding sense controls, whereas notch-2, notch-3, jagged-1, or jagged-2 antisense oligos had no significant effect. To assess cell differentiation, we immunostained lung bud cultures for the neural/neuroendocrine marker PGP9.5. Antisense to notch-1 or jagged-1 markedly increased numbers of PGP9.5-positive neuroendocrine cells alone without affecting neural tissue, whereas only neural tissue was promoted by notch-3 antisense in culture. There was no significant effect on cell proliferation or apoptosis in these antisense experiments. Cumulatively, these observations suggest that interactions between distinct Notch family members can have diverse tissue-specific regulatory functions during development, arguing against simple functional redundancy.

Analysis of Variance↗
PubMed1995

Role of vitamin A in lung development.

There is good rationale for presuming a role for vitamin A in lung development. In situ studies have demonstrated that certain retinoic acid (RA) receptor proteins are localized in a specific fashion during fetal lung branching and airway growth. Vitamin A stores are high in fetal lung and decrease toward term, possibly being utilized for changes in lung morphogenic remodeling. The binding activity, levels and expression of the cytosolic and nuclear receptor proteins for vitamin A undergo changes before and after birth in rat lung. RA slows fetal Type II cell proliferation in culture but stimulates choline incorporation into phosphatidylcholine. RA can regulate several other factors involved in lung development such as homeobox genes, matrix molecules and certain growth factors. Further study is needed on this potential functional role of RA in lung. Retinol deficiency results in lung histopathology that is similar to bronchopulmonary dysplasia, which occurs frequently in human premature neonates. Clinical trials are attempting to define the role of supplementation of vitamin A in the prevention and treatment of that condition.

Animals↗
PubMed1986

Lung development in the marsupial bandicoot, Isoodon macrourus.

The transformation of the terminal sacs present in the newborn into the alveoli observed in the adult, and the tissue and cellular composition of the interalveolar septum at various stages of lung development, were examined in the developing bandicoot. Lungs from 22 bandicoots, aged from 1 day postpartum to adult, were fixed with a glutaraldehyde/formaldehyde fixative and processed for examination of their structure. The respiratory region of the newborn lung is formed from terminating sacs, approximately 300-500 microns in diameter, which are delineated by thick connective tissue septa, have a highly vascularised internal lining and are present from birth until approximately Day 35 postpartum. The large blind sacs are then gradually replaced by alveoli, approximately 80 microns in diameter. In the juvenile and adult bandicoot, the connective tissue septa of the sacs are no longer discernible and a larger area of the blood capillaries of the lung is adjacent to the air within the alveoli. The changes in lung structure throughout pouch life probably reflect the increased respiratory requirements of the developing young. Although the time sequence of lung development in the eutherian differs from that in the marsupial, the adult form of the lung in both animal groups is similar in structure.

Animals↗
PubMed2001

Transcription factors in mouse lung development and function.

Development of the mouse lung initiates on day 9.5 postcoitum from the laryngotracheal groove and involves mesenchymal-epithelial interactions, in particular, those between the splanchnic mesoderm and epithelial cells (derived from foregut endoderm) that induce cellular proliferation, migration, and differentiation, resulting in branching morphogenesis. This developmental process mediates formation of the pulmonary bronchiole tree and integrates a terminal alveolar region with an extensive endothelial capillary bed, which facilitates efficient gas exchange with the circulatory system. The major function of the mesenchymal-epithelial signaling is to potentiate the activity or expression of cell type-specific transcription factors in the developing lung, which, in turn, cooperatively bind to distinct promoter regions and activate target gene expression. In this review, we focus on the role of transcription factors in lung morphogenesis and the maintenance of differentiated gene expression. These lung transcription factors include forkhead box A2 [also known as hepatocyte nuclear factor (HNF)-3beta], HNF-3/forkhead homolog (HFH)-8 [also known as FoxF1 or forkhead-related activator-1], HNF-3/forkhead homolog-4 (also known as FoxJ1), thyroid transcription factor-1 (Nkx2.1), and homeodomain box A5 transcription factors, the zinc finger Gli (mouse homologs of the Drosophila cubitus interruptus) and GATA transcription factors, and the basic helix-loop-helix Pod1 transcription factor. We summarize the phenotypes of transgenic and knockout mouse models, which define important functions of these transcription factors in cellular differentiation and lung branching morphogenesis.

Amino Acid Motifs↗
PubMedDate not supplied

Effect of lung development on the histological pattern of lung tumors induced by ethylnitrosourea in the C3HeB/FeJ mouse.

The number, size, and histological pattern of lung tumors collected 6 months after being induced in C3HeB/FeJ mice by ethylnitrosourea (ENU) treatment on one of days 13-19 of gestation, or days 5, 15, or 35 after birth, or as 9-month-old adults was investigated. The number of lung tumors induced increased when treatment occurred between days 13-16 and then decreased when treatment occurred on days 17-19 of gestation. There was a marked increase in lung tumor numbers induced on day 5 after birth, which decreased to much lower levels on days 15 and 35 after birth and in the treated adult mice. The size of lung tumors was greater in males than females in all groups and decreased as the age at the time of ENU treatment increased. A greater proportion (60-65%) of papillary tumors were induced following treatment on days 13-16 whereas, with one exception, alveolar lining tumors were the predominant histological type when treatment occurred after day 16. When treatment occurred on day 5 after birth, papillary tumors were once again the predominant type (66%) induced. The changes in tumor numbers induced and in the histological type of tumor induced occur at periods when major shifts in the histological development of the lung occur. The results indicate that the histological type of tumor induced by ENU treatment is developmentally regulated and suggests that alveolar lining and papillary tumors behave as two separate populations of tumors.

Animals↗
PubMed2005

Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development?

Congenital diaphragmatic hernia (CDH) usually occurs sporadically. The prognosis remains poor, with a 50% perinatal mortality rate. Most deaths result from hypoxemia due to lung hypoplasia and abnormal development of pulmonary vasculature that results in persistent pulmonary hypertension. Our current understanding of the pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. Pulmonary hypoplasia, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Moreover, a nitrofen-induced CDH model shows that lung hypoplasia precedes the diaphragmatic defect, leading to a "dual-hit hypothesis." Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the clinical and epidemiological aspects of human CDH, the metabolic and molecular aspects of the retinoid-signaling pathway, and the implications of retinoids in the development of the diaphragm and the lung. Finally, we highlight the existing links between CDH and disruption of the retinoid-signaling pathway, which may suggest an eventual use of retinoids in the treatment of CDH.

Animals↗
PubMed1984

Modifying risk of developing lung cancer by changing habits of cigarette smoking.

Data from a hospital based case-control study of lung cancer in Western Europe were used to examine changes in the risk of developing lung cancer after changes in habits of cigarette smoking. Only data for subjects who had smoked regularly at some time in their lives were included. The large size of the study population (7181 patients and 11 006 controls) permitted precise estimates of the effect of giving up smoking. Risks of developing lung cancer for people who had given up smoking 10 or more years before interview were less than half of those for people who continued to smoke. The reduction in risk was seen in men and women and in former smokers of both filter and non-filter cigarettes but varied by duration of smoking habit before giving up. The protective effect of giving up became progressively greater with shorter duration of smoking habit. The risks after not smoking for 10 years for both men and women who had previously smoked for less than 20 years were roughly the same as those for lifelong non-smokers. Reducing the number of cigarettes smoked a day or switching from non-filter to filter cigarettes also lowered the risk of developing lung cancer but not to the extent associated with giving up smoking.

Europe↗
PubMed1994

Perinatal lung development following maternal exposure to methylmercuric chloride.

Mercury ingested from dietary sources has potent neurotoxic and teratogenic effects. Initial studies have shown that mercury may also affect fetal lung development. Since these pulmonary effects may play a role in subsequent neonatal morbidity and mortality due to compromising of the development of the lung, mercury effects in fetal and neonatal lung were investigated. Methylmercuric chloride (MMC), 1,000 ppm (15 mg/kg of body weight); was administered via an intragastric tube to timed-pregnant Swiss/Webster mice on day 9 of gestation. Lungs from fetuses on gestational day 18 and from neonates on days 1, 5, or 10 after birth were studied. Significant changes in MMC-exposed lungs compared to controls occurred at postnatal day 1. At this time, lung weight per gram body weight increased, phospholipid content per gram of lung or per microgram of DNA decreased, while DNA per gram of lung increased. Methylmercury appears to have delayed lung maturation. Cuboidal epithelial cells in alveolar tubules contained conspicuous glycogen deposits, and differentiation of alveolar type II cells was adversely affected. These results suggest that prenatal exposure to methylmercury may be detrimental to lung development, specifically to the initiation of surfactant synthesis, by delaying the normal pattern of maturation of the alveolar type II cells within the lungs.

Animals↗
PubMed1989

Meclofenamate does not affect lung development in fetal sheep.

Prostaglandins may be involved in some aspects of fetal lung development, including surfactant metabolism, tracheal fluid production, and possibly lung growth. In the fetus, during the days before delivery, plasma PGE2 concentration increases and concurrently, tracheal fluid production decreases and surfactant production increases. To determine whether the increase in PGE2, specifically plasma PGE2 concentration, is responsible for these changes, we continuously infused the prostaglandin synthetase inhibitor, meclofenamate (0.7 mg/h per kg), into 8 fetal sheep for 5-13 days before delivery; 5 control fetuses received a continuous infusion of solvent for 5-11 days before delivery. Meclofenamate infusion significantly decreased plasma PGE2 concentrations until the day of delivery. However, meclofenamate did not affect tracheal fluid production or its decrease before delivery, fetal plasma cortisol concentration, surfactant content of tracheal fluid and lung tissue, organ weights, lung weights, or lung DNA and protein content. We conclude that the changes in lung development during the days before delivery are not dependent on the usual high fetal plasma concentration of PGE2 or its increase before delivery.

Animals↗
PubMed1996

Pulmonary Neuroendocrine Cells and Lung Development.

Pulmonary neuroendocrine cells produce bioactive peptides such as gastrin-releasing peptide (GRP) at high levels in developing fetal lung. The role of GRP and other peptides in promoting branching morphogenesis, cell proliferation, and cell differentiation during lung organogenesis is reviewed. Possible roles for bioactive peptides derived from these cells in the pathophysiology of perinatal lung disorders are discussed.

Journal Article↗
PubMed1986

Effect of induced oligohydramnios on fetal lung development.

To investigate the impact of oligohydramnios on fetal growth, development, and lung function, amniotic fluid was shunted from alternate gestational sacs into the maternal peritoneal cavity at 23 days' gestation in the fetal rabbit. Uninstrumented fetuses served as controls. Oligohydramnios was confirmed at the time of planned cesarean delivery on either day 26 or 28. Fetuses subjected to prolonged oligohydramnios had significantly decreased body weight at 26 (p = 0.002) and 28 days (p = 0.007). Similarly, lung weight was decreased at 26 (p = 0.02) and 28 days (p = 0.005). There was a trend toward decreased maximum lung volume for instrumented fetuses at 28 days (p = 0.07). Deflation limbs of the pressure-volume curves revealed significantly increased air trapping for instrumented fetuses at 28 days. These studies suggest not only a detrimental effect of oligohydramnios on fetal body and lung weight but also a beneficial effect of premature rupture of membranes on fetal lung function. Analysis of phospholipid and histologic changes is currently under way.

Amniotic Fluid↗
PubMed1987

Lung development under the influence of thiourea and L-thyroxine. Retarding and toxic effects of thiourea.

Chick embryos were treated on day 17 of incubation with 32.8 mumol thiourea or 18.9 nmol L-thyroxine. As was already known from previous studies, hatching was delayed and accelerated, respectively, under these conditions. The premature induction of hatching by L-thyroxine was accompanied by an advanced development of the pulmonary structure and of the circulation and by a premature absorption of the parabronchial liquid. Thiourea exerted an opposite effect on these parameters. In several cases the structural formation of the parabronchii was suppressed after treatment with thiourea. Furthermore, parabronchial liquid accumulated in those embryos, the hatching of which was suppressed. It is suggested that these changes represent a toxic effect of thiourea rather than a retardation of pulmonary development.

Animals↗
PubMed1980

Hormonal influences during fetal lung development.

Maturation of the fetal lung is accelerated by in utero treatment with corticosteroids and thyroid hormones. Other agents such as catecholamines, thyrotropin-releasing hormone, oestradiol, heroin and cyclic AMP also influence pulmonary phospholipid metabolism. Glucocorticoids cause precocious development of both lung morphology and the surfactant system in type II cells, resulting in more stable lungs with increased air space. The properties of glucocorticoid action are consistent with enzyme induction mediated by interaction of steroid with cytoplasmic glucocorticoid receptors. Receptors are present in lung of many species, including the human fetus, and in both pulmonary fibroblasts and type II cells. Corticosteroid therapy of women in premature labour is currently used to reduce the incidence of infant respiratory distress syndrome (RDS). Treatment of the mother with 12 mg betamethasone causes an approximately four-fold maximal increase in unbound glucocorticoid activity in fetal plasma which is calculated to cause 80% nuclear occupancy by receptor-steroid complex. It is likely that endogenous corticoids influence normal lung development; possible sources of cortisol include the fetal adrenal, maternal adrenal, and conversion of cortisone to cortisol by amniotic membranes and lung fibroblasts. Thyroid hormones have effects similar to corticosteroids, but appear to influence different biochemical steps. Synthetic analogues of triiodothyronine (T3) are available which readily cross the placenta, in contrast to T3 and thyroxine, and accelerate surfactant synthesis and release. Thyroid hormones probably act through nuclear receptors which are present in lung of both animals and the human. Thyroid treatment in utero also appears to accelerate lung maturation and prevent RDS in premature infants.

Animals↗
PubMed1994

A rhesus monkey model to characterize the role of gastrin-releasing peptide (GRP) in lung development. Evidence for stimulation of airway growth.

Gastrin-releasing peptide (GRP) is developmentally expressed in human fetal lung and is a growth factor for normal and neoplastic lung but its role in normal lung development has yet to be clearly defined. In this study we have characterized the expression of GRP and its receptor in fetal rhesus monkey lung and determined the effects of bombesin on fetal lung development in vitro. By RNA blot analysis, GRP mRNA was first detectable in fetal monkey lung at 63 days gestation, reached highest levels at 80 days gestation, and then declined to near adult levels by 120 days gestation; a pattern closely paralleling GRP expression in human fetal lung. As in human lung, in situ hybridization localized GRP mRNA to neuroendocrine cells though during the canalicular phase of development (between 63-80 days gestation) GRP mRNA was present not only in classic pulmonary neuroendocrine cells, but also in cells of budding airways. Immunohistochemistry showed that bombesin-like immunoreactivity was present in neuroendocrine cells, but not in budding airways, suggesting that in budding airways either the GRP mRNA is not translated, is rapidly secreted, or a related, but different RNA is present. RNase protection analysis using a probe to the monkey GRP receptor demonstrated that the time course of receptor RNA expression closely paralleled the time course of GRP RNA expression. In situ hybridization showed that GRP receptors were primarily expressed in epithelial cells of the developing airways. Thus GRP would appear to be secreted from neuroendocrine cells to act on target cells in developing airways. This hypothesis was confirmed by organ culture of fetal monkey lung in the presence of bombesin and bombesin antagonists. Bombesin treatment at 1 and 10 nM significantly increased DNA synthesis in airway epithelial cells and significantly increased the number and size of airways in cultured fetal lung. In fact, culturing 60 d fetal lung for 5 d with 10 nM bombesin increased airway size and number nearly to that observed in cultured 80 d fetal lung. The effects of bombesin could be blocked by specific GRP receptor antagonists. Thus this study demonstrates that GRP receptors are expressed on airway epithelial cells in developing fetal lung and that the interaction of GRP with the GRP receptor stimulates airway development.

Amino Acid Sequence↗
PubMed1989

Immunotargeting: a contemporary approach to the study of lung development.

This commentary discusses an immunological approach to lung development that has been termed immunotargeting. The approach involves the use of monoclonal antibody technology to identify cell membrane antigens unique to cells of particular lineage or stage of differentiation. Methods of using the antibodies to focus on important unresolved questions relating to development, particularly of the pulmonary epithelium, are discussed. Antigens and membrane molecules, which have already been identified and which may be useful in this type of approach to respiratory epithelial cell differentiation, are enumerated and briefly described.

Aging↗
PubMed1993

CD44 positive macrophages take up hyaluronan during lung development.

In the present study, we examined the expression and distribution of both hyaluronan and its cell-surface receptor (CD44) during lung development in the mouse. Hyaluronan was detected by a specific binding probe, termed b-PG, which is a biotinylated mixture of proteoglycan and link protein from cartilage. Using this probe in an enzyme-linked assay, the amount of hyaluronan in relation to protein content was found to decrease as lung development progressed. In addition, histochemical staining of the embryonic lungs revealed that during early stages, relatively large amounts of hyaluronan were present in the interstitium. However, as development progressed, much of this was lost, and in the adult, hyaluronan was restricted to the regions surrounding the major blood vessels, bronchi, and bronchioles. In contrast to hyaluronan, the amount of CD44 increased as a function of development, as determined by the rat monoclonal antibody, KM-201. Histochemical staining with this antibody showed that the receptor was primarily associated with macrophages and to a lesser extent with adult bronchial and bronchiolar epithelium, vascular smooth muscle, and endothelial cells. As development progressed, the macrophages expressing CD44 increased in number, and this increase was temporarily correlated with the decrease in hyaluronan content. In addition, histochemical staining revealed that some of these macrophages contained hyaluronan in their cytoplasm, suggesting that macrophages had internalized hyaluronan from the extracellular matrix. This possibility was further supported by the fact that when newborn mice were injected with the KM-201 monoclonal antibody, which blocks the interaction between hyaluronan and the receptor, the number of hyaluronan-containing macrophages in the lungs decreased while the concentration of hyaluronan increased. Taken together, these results suggest that macrophages can internalize hyaluronan during lung development and could possibly play a significant role in its removal.

3T3 Cells↗