Immunological study of lung development in the mouse embryo. II. First appearance of the great alveolar cell, as shown by immunofluorescence microscopy.
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Animals↗
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Angiotensin-converting enzyme in developing lung and kidney.
Angiontensin-converting enzyme (ACE) catalyzes rapid conversion of angiotensin II (AII). This enzyme has been identified in the vascular endothelium of nearly every tissue. Inasmuch as AII is the biologically active component of the renin-angiotensin system, and since age-related differences exist in the renin-angiotensin system, it was of interest to determine converting enzyme activity during development. ACE activity was quantified by measuring the optical density of hippuric acid liberated from hippuryl-L-histidyl-L-leucine (HHL) following incubation with the 20,000 X g supernatant of tissue homogenates. Pulmonary ACE activity of near-term fetal rats was not different than 1-day-old animals. Therafter, ACE activity increased during the first 6 wk postpartum in a biphasic manner. A similar age-dependent increase in converting enzyme activity was observed in rat kidney, mouse kidney, and mouse lung. Substrate affinity of all enzymes measured was similar, suggesting that the age-related increase in activity was due to increased enzyme content. The low activity of ACE in the newborn might function to limit AII production.
Aging↗
Lung development in the fetal primate, Macaca nemestrina. II. Pressure-volume and phospholipid changes.
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Amniotic Fluid↗
Lung development in the fetal primate Macaca nemestrina. I. Growth and compositional changes.
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Animals↗
Collagen and non-collagen protein synthesis in developing lung exposed to tobacco smoke.
The present investigation was conducted to determine the rate of collagen and non-collagen protein synthesis by rat lung under in vitro conditions. The rate of synthesis of non-collagen protein was greater than the rate of collagen synthesis in animals between 1 and 95 days of age. Synthesis of both types of proteins was highest in 1-day-old animals. Rate of synthesis of non-collagen protein was markedly diminished after 7 days of age and that of collagen decreased after 14 days. Per gram lung, the total amount of collagen increased 3.5-fold between Day 7 and 95 whereas total protein was relatively constant. When lung was exposed to smoke under in vitro conditions synthesis of collagen and non-collagen protein was almost completely depressed.
Age Factors↗
Phospholipid biosynthesis: the activity of phosphatidic acid phosphohydrolase in the developing lung and amnionic fluid.
The presented data suggest that PAPase may, indeed, be important in the biosynthesis of lung phospholipids. The observed increase in the specific activity of rabbit lung precedes the "surge" of phosphatidylcholine concentration and surfactant biosynthesis by at least 24 hours. In human amnionic fluid, PAPase specific activity was markedly increased in pregnancies of 35 weeks of gestation or more. The increase in the specific activity of PAPase preceded the "surge" of acetone precipitated phosphatidylcholine. The reported studies may provide an additional procedure to examine the problems associated with surfactant biosynthesis.
Amniotic Fluid↗
Structural aspects of gas exchange.
The lung is composed of several million small air spaces, lined by a delicate tissue membrane separating air from capillary blood. The design features of the gas exchange region in the lung are optimal for gaseous diffusion, by having a very extensive contact surface but with a minimal tissue barrier composed of an epithelial and endothelial layer separating an interstitial layer. The extent of the gas exchange surface in adult lungs is determined by general maturation which in turn is influenced by metabolic requirements of the organism. Environmental factors can modulate the pattern of ultimate lung development. Lung inflation causes air spaces to expand mainly by a process of tissue unfolding beneath an extremely thin layer of alveolar surfactant. This ensures cellular integrity during extreme deformations while at the same time providing a reserve of gas exchange surface so that functional diffusion capacity at all lung volumes is less than the structural maximum.
Animals↗
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↗
Changes in the structural and metabolic heterogeneity of phosphatidylcholines in the developing rat lung.
In the present study the developmental profiles of the structural and metabolic heterogeneity of rat lung phosphatidylcholine are presented. The individual molecular species of phosphatidylcholine at different stages of the developing rat lung were analyzed as diacylglycerol derivatives. The metabolic heterogeneity of rat lung phosphatidylcholine was also studied by incubation using lung slices with radioactive precursors. The results obtained were as follows: 1. A significant increase of lung phosphatidylcholine during perinatal development (up to 1 day after birth) was found to be largely due to the increase of dipalmitoyl species. The percentage of palmitoyl-palmitoleoyl species also increased from --4 to --1 day of gestation, while palmitoyl-oleoyl species were found to decrease during development. Other molecular species showed no significant changes. 2. The incorporation of [1-14C]palmitoyl lysophosphatidylcholine into saturated phosphatidylcholine was relatively low at the earlier stage of fetal development, but it increased significantly in the last stage and reached its maximum at one day prior to birth and one day prior to the marked accumulation of dipalmitoylphosphatidylcholine occurring in the lung. In contrast, the incorporation of [3H]glycerol into saturated phosphatidylcholine remained, without showing a marked alteration during development. These results suggest that the lysophosphatidylcholine pathway which is mainly attributed to transacylation mechanism between 2 molecules of lysophosphatidylcholine may contribute to the marked production of dipalmitoylphosphatidylcholine in the lung in the last stage of gestation.
Aging↗
Role of cyclic AMP and related enzymes in rat lung growth and development.
Cyclic AMP levels in rat lungs showed phasic elevations which peaked during fetal, neonatal and late postnatal periods of development. Lung phospholipids showed major alterations in their levels during fetal and early neonatal life. Alterations in glycogen levels were accompanied by parallel changes in phosphorylase a/total phosphorylase activity which may be related to changes in cyclic AMP during development. Cyclic AMP levels were dependent on the relative activities of adenylate cyclase and cyclic AMP phosphodiesterase which also changed with age. Activation of adenylate cyclase by norepinephrine and NaF, and of cyclic AMP phosphodiesterase by calcium, was maximum neonatally and declined variably thereafter. These data suggest a relationship between cyclic AMP, glycogen and phospholipids during rat lung development.
3',5'-Cyclic-AMP Phosphodiesterases↗
Activity of cholinephosphotransferase, lysolecithin: lysolecithin acyltransferase and lysolecithin acyltransferase in the developing mouse lung.
1. The present study presents the activity profiles of cholinephosphotransferase, lysolecithin:lysolecithin acyltransferase and lysolecithin acyltransferase at different stages of development of the mouse lung. 2. The specific activity of cholinephosphotransferase, a key enzyme in the de novo synthesis of phosphatidylcholine, increases during the later stages of fetal development until it reaches a maximal value at a gestational age of 17 days, i.e. 2 days before term. Thereafter, the activity of the enzyme declines again until around term. 2. The specific activity of lysolecithin:lysolecithin acyltransferase which catalyzes the transesterification between two molecules of 1-acyl-sn-glycero-3-phosphocholine, appears to be much lower than that of cholinephosphotransferase at gestational ages below 18 days. However, around day 18, the specific activity of lysolecithin:lysolecithin acyltransferase increases dramatically until it almost equals the maximal activity of cholinephosphotransferase measured on day 17. 4. The specific activity of lysolecithin acyltransferase, which catalyzes the direct acylation of 1-acyl-sn-glycero-3-phosphocholine, does not change significantly during the prenatal development and is lower than that of either lysolecithin:lysolecithin acyltransferase or cholinephosphotransferase at all stages of development. 5. These results are discussed in view of the possible role of these enzymes in the biosynthesis of pulmonary 1,2-dipalmitoyl-sn-glycero-3-phosphocholine.
1-Acylglycerophosphocholine O-Acyltransferase↗
Metabolic activity of developing rabbit lung.
The uptake and metabolism of [3H]leucine, [U-14C]glucose, and [3H]palmitate were studied in rabbits aged --3, 1, 7, 28, and 90 days up to 1--1.5 years. Although lung composition did not change markedly, there were great differences in lung metabolism between the perinatal period (late fetal and newborn) and later stages of development. Leucine incorporation into lung protein was highest (3.1--3.4 nmol/mg protein/hr) in late fetal and newborn rabbits and decreased rapidly thereafter. Palmitic acid incorporation decreased during the first week after birth from 150 nmol/100 mg/hr to 85 nmol/100 mg/hr at 7 days of age; it increased thereafter to 170 nmol/100 mg/hr at 4 weeks of age and remained at that level throughout the entire period studied. Glucose uptake and lactate production were higher in fetal lungs than in all other age groups. Lipid biosynthesis from glucose was 2--4 times higher in fetal lungs than at all other ages; furthermore, more than 60% of glucose carbon atoms channeled into lipid was incorporated into fatty acids, whereas at all other ages glucose was chiefly a precursor of lipid glycerol.
Animals↗
Tumor development in lung of ddY mice following transplacental exposure to 1-ethyl-1-nitrosourea.
Transplacental induction of lung tumor by 1-ethyl-1-nitrosourea (ENU) was studied in pregnant ddY mice which were given a single intraperitoneal injection of 58.5 mg/kg of ENU in water between day 13 and 19 of gestation. Within 4 approximately 6 weeks after birth, pulmonary tumor nodules were found in all offsprings exposed to ENU, and they were histopathologically adenoma. Number of tumor nodules could be counted under the stereomicroscope from approximately day 40 after birth. The size of tumor increased with the lapse of time but the number of tumor nodules did not increase markedly. Weekly injections of urethan or ENU into mice pretreated with ENU in their fetal age enhanced the number of pulmonary adenoma. The development of other tumor was not seen except a few cases of lymphoma. Tumor development in the lung by injection of ENU in ddY mice during gestation is reproducible, relatively simple, and rapid. Therefore, it is considered that this may be a useful method for screening of antitumor agent.
Adenoma↗
TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.
Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.
Humans↗
Acceleration of canalicular development in lungs of fetal mice exposed transplacentally to dexamethasone.
Morphometric techniques were used to compare the volume density of air space (Vva) and the degree of maturation of pulmonary epithelium in normal fetal mouse lung and in lungs of fetuses exposed transplacentally to dexamethasone. Pregnant Bagg-Webster Swiss mice of 16 days' gestation were given injections of either saline or dexamethasone in doses ranging from 0.40 to 12.0 microng. per gm. of body weight, and killed at intervals thereafter. Fetuses were removed and weighed and their lungs prepared for morphometry using osmium-fixed, Epon-embedded tissue. In control lungs, Vva increased 10-fold between days 17 and 19, an increase from 1.5 to 15%. A 25-fold increase occurred during the same period in test fetal lungs exposed to 0.40 microng. per gm. or more of dexamethasone. When the degree of air space development was compared 24 hours after exposure, within a single weight group and, according to dose, a linear increase in air space was found; 0.1-microng. per gm. increment in dexamethasone produced a 0.66% increment in Vva. Body weight was an important determinant, in that fetuses in the lower weight range had much less response. The latter showed an increment of approximately 0.25% in Vva for each 0.1-microng. per gm. increment of dexamethasone. It can be emphasized from the present experiments that a maximal development of Vva could be achieved by amounts of dexamethasone too low to depress fetal or lung weight. The proportion of pulmonary epithelial cells containing osmiophilic granules increased in control lungs from 18% on day 17 to 42% on day 18. Test fetuses (17 days old) examined 24 hours after receiving either 0.40 or 0.80 microng. per mg. of dexamethasone showed no significant increase in this proportion; however, a significant increase in the proportion of cells containing osmiophilic granules was found in fetal lungs exposed to 2.0 microng. per mg. Whereas a significant increase in Vva was found within 14 hours of exposure, no increase in the proportion of cells containig osmiophilic granules was detectable at this time. It was concluded that air space development is a sensitive method for evaluating the effect of dexamethasone as it gives a clear dose-response curve in fetuses exposed to it 24 hours prior to sacrifice. Accelerated maturation of the presumptive type II cell could only be demonstrated within 24 hours by using higher doses than those required to initiate air space development. These observations suggest that the steps invovled in canal formation, which are assumed to reflect alterations in mesenchyme, may have a different sensitivity to dexamethasone than do those initiating the maturation of alveolar epithelial cells.
Animals↗
Blood gas tension and development of lung damage in mice exposed to oxygen at 1 ATA.
Oxygen and carbon dioxide tension in arterial blood were studied in mice breathing 100% oxygen at ambient pressure. The lungs were simultaneously investigated in order to relate the oxygen-induced pulmonary alterations to the altered pulmonary function. The development of an impairment in pulmonary diffusing capacity is initiated after 30 h of oxygen exposure, at which time the increase in lung weight is associated with beginning lung edema and beginning accumulation of carbon dioxide in the blood. Red spots or areas on the lung surface, which merged together to large streaks or areas after 20 h of exposure, preceded the measurable diffusing impairment noted at 30 h. Light microscope preparations revealed intraalveolar hemorrhagic exudation and proliferative changes in the alveolar walls. After 50 h, the development of severe pulmonary dysfunction is mainly due to an intense parenchymal reaction in the alveolo-capillary region with thickening in the alveolar walls, dystelectasis in the corresponding parenchyma, and further development of pulmonary edema. The resulting impairment in pulmonary diffusing capacity causes a steep decrease in oxygen tension and an accentuated increase in carbon dioxide accumulation. The present results are discussed in relation to the previous findings of oxygen-induced alterations in brain glutamate, GABA, and glutamine concentration.
Animals↗
Toxic effects of cadmium on the developing rat lung. I. Altered pulmonary surfactant and the induction of respiratory distress syndrome.
The effects of Cd on the growth of the fetal rat lung and the maturation of the pulmonary surfactant system were studied. Pregnant rats received sc injections of cadmium chloride on d 12-15 of gestation. Animals were sacrificed throughout late gestation. Fetal lungs were assayed for pulmonary surfactant lecithin and spingomyelin. Some animals were allowed to give birth and the neonates were observed for symptoms of respiratory distress. The treatment resulted in high fetal mortality and growth retardation. Lung-body weight ratios were reduced by 20-30% in treated fetuses. Pulmonary spingomyelin content was not affected by the Cd absolute quantity but not in lecithin-lung weight ratio on the last days of gestation. Parturition was delayed almost a full day by the Dd treatment, and birth weights were reduced. Of the treated neonates, 11% developed respiratory distress syndrome. All but one of these individuals died and had lungs with hyaline membranes. Prenatal exposure to Cd can (1) cause lung hypoplasia, (2) affect pulmonary surfactant, and (3) induce respiratory distress syndrome in term pups.
Animals↗
Acetylcholinesterase- and norepinephrine- containing nerves in developing rat lung.
The lungs of rat fetuses at various stages of gestation and lungs of infant rats were examined histochemically for acetylcholinesterase (AChE) and norepinephrine (NE). No AChE is present in the fetal lungs until 15 days of gestation. At this stage a number of large round cells appear which stain heavily for AChE. These cells disappear by the 18th day of development and at 18 days no AChE-positive structures are demonstrable within the lung. The large AChE-positive cells are of similar size and distribution to fluorescent cells which become apparent after treatment of the mothers with L-DOPA. At 20 days, the day before delivery, a diffuse AChE reaction appears in the walls of large branches of intrapulmonary bronchi. At 20 days, also, sparse NE-containing nerves are present near the hilum and extend along bronchial arteries into the lung. Not until birth do AChE-containing nerves appear in intrathoracic structures. These are vagal preganglionic and postganglionic fibers near the trachea, bronchi, and esophagus. AChE-positive ganglion cells are present in the walls of extrapulmonary bronchi at birth, and perimuscular nerve plexuses containing AChE are also present in the bronchial walls. NE-containing nerves are visible in several divisions of the bronchial artery at birth. Three days postnatally, AChE-containing nerves have not yet invaded intrapulmonary structures, but at this stage the adult pattern of adrenergic innervation is present. By the fifth postnatal day, sparse AChE-positive nerves are associated with intrapulmonary bronchi, and rats 9 days old present the adult pattern of cholinesterase-containing nerves.
Acetylcholinesterase↗