Pre- and Postnatal Lung Development, Maturation, and Plasticity Distal air space epithelial fluid clearance in near-term rat fetuses is fast and requires endogenous catecholamines (original) (raw)
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2002
Oligohydramnios (OH) retards fetal lung growth by producing less lung distension than normal. To examine effects of decreased distension on fetal lung development, we produced OH in rats by puncture of uterus and fetal membranes at 16 days of gestation; fetuses were delivered at 21 or 22 days of gestation. Controls were position-matched littermates in the opposite uterine horn. OH lungs had lower weights and less DNA, protein, and water, but no differences in saturated phosphatidylcholine, surfactant proteins (SP)-A and-B, and mRNA for SPA ,-B,-C, and-D. To evaluate effects on epithelial differentiation, we used RTI 40 and RTII70, proteins specific in lung to luminal surfaces of alveolar type I and II cells, respectively. At 22 days of gestation, OH lungs had less RTI40 mRNA (P Ͻ 0.05) and protein (P Ͻ 0.001), but RTII70 did not differ from controls. With OH, type I cells (in proportion to type II cells) covered less distal air space perimeter (P Ͻ 0.01). We conclude that OH, which retards lung growth, has little effect on surfactant and impedes formation of type I cells relative to type II cells.
American Journal of Physiology Lung Cellular and Molecular Physiology, 2002
Oligohydramnios (OH) retards fetal lung growth by producing less lung distension than normal. To examine effects of decreased distension on fetal lung development, we produced OH in rats by puncture of uterus and fetal membranes at 16 days of gestation; fetuses were delivered at 21 or 22 days of gestation. Controls were position-matched littermates in the opposite uterine horn. OH lungs had lower weights and less DNA, protein, and water, but no differences in saturated phosphatidylcholine, surfactant proteins (SP)-A and-B, and mRNA for SPA ,-B,-C, and-D. To evaluate effects on epithelial differentiation, we used RTI 40 and RTII70, proteins specific in lung to luminal surfaces of alveolar type I and II cells, respectively. At 22 days of gestation, OH lungs had less RTI40 mRNA (P Ͻ 0.05) and protein (P Ͻ 0.001), but RTII70 did not differ from controls. With OH, type I cells (in proportion to type II cells) covered less distal air space perimeter (P Ͻ 0.01). We conclude that OH, which retards lung growth, has little effect on surfactant and impedes formation of type I cells relative to type II cells.
Effects of oligohydramnios on lung growth and maturation in the fetal rat
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2002
Oligohydramnios (OH) retards fetal lung growth by producing less lung distension than normal. To examine effects of decreased distension on fetal lung development, we produced OH in rats by puncture of uterus and fetal membranes at 16 days of gestation; fetuses were delivered at 21 or 22 days of gestation. Controls were position-matched littermates in the opposite uterine horn. OH lungs had lower weights and less DNA, protein, and water, but no differences in saturated phosphatidylcholine, surfactant proteins (SP)-A and -B, and mRNA for SP-A, -B, -C, and -D. To evaluate effects on epithelial differentiation, we used RTI40and RTII70, proteins specific in lung to luminal surfaces of alveolar type I and II cells, respectively. At 22 days of gestation, OH lungs had less RTI40mRNA ( P < 0.05) and protein ( P < 0.001), but RTII70did not differ from controls. With OH, type I cells (in proportion to type II cells) covered less distal air space perimeter ( P < 0.01). We conclude tha...
Journal of Biological Chemistry, 2008
Neonatal respiratory distress syndrome (RDS) is mainly the result of perturbation in surfactant production and is a common complication seen in premature infants. Normal fetal lung development and alveolar cell differentiation is regulated by a network of transcription factors. Functional loss of any of these factors will alter the developmental program and impact surfactant production and normal gas exchange. During development, the fetus is exposed to varying oxygen concentrations and must be able to quickly adapt to these changes in order to survive. Hypoxia-inducible factor 1␣ (HIF1␣) is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension and is essential for normal development. Its role in lung maturation is not well defined and to address this knowledge gap, a lung-specific HIF1␣ knockout model has been developed. Loss of HIF1␣ early in lung development leads to pups that die within hours of parturition, exhibiting symptoms similar to RDS. Lungs from these pups display impaired alveolar epithelial differentiation and an almost complete loss of surfactant protein expression. Ultrastructural analysis of lungs from HIF1␣ deletion pups had high levels of glycogen, aberrant septal development, and decreased expression of several factors necessary for proper lung development, including HIF2␣, -catenin, and vascular endothelial growth factor. These results suggest that HIF1␣ is essential for proper lung maturation and alteration in its normal signaling during premature delivery might explain the pathophysiology of neonatal RDS. During development, an embryo is exposed to varying levels of oxygen as a balance is created between vascularization and tissue growth. Localized hypoxia, a decrease in available oxygen, is a normal part of this process. The programmed responses to these decreases in available oxygen are essential for viability (1, 2). In utero, the embryo is supplied with oxygen and nutrients through the placental barrier. Following parturition, oxygen is supplied by the neonatal lungs and therefore, proper intrauterine development of the alveolar gas exchange regions of the lung is essential for the newborn's first breath and for sustaining life outside the womb (3). Lung morphogenesis is a complex process that is orchestrated by several transcription factors, growth factors, and extracellular cues (4). For example, thyroid transcription factor-1 regulates the expression of the genes for Clara cell secretory protein (CCSP) 2 produced in Clara cells in the tracheobronchial airways and various surfactants produced by alveolar type II cells in the lung parenchyma (5, 6). CCAAT-enhancerbinding protein ␣ (CEBP␣) is essential for proper regulation of alveolar Type II cell differentiation, and Forkhead box A2 (Foxa2) controls various cellular programs involved in lung development (e.g. surfactant expression) (6-8). Ablation of any of these factors results in major structural and functional abnormalities ranging from undeveloped alveolar structure and/or improper airway branching to the faulty processing of various secretory components (7, 8). One of the extracellular cues that is important for fetal vascular growth and lung morphogenesis is the physiologically low O 2 environment of the fetus. The ability to cope with this developmental "hypoxia" is not only important for lung maturation but essential for the viability of the fetus (1, 2). Cellular responses to decreased oxygen availability are regulated by a family of proteins called hypoxia-inducible factors (HIFs). The ability of HIFs to respond to hypoxia is controlled by oxygen-dependent post-translational hydroxylation. The prolyl hydroxylases, PHDs, modify HIFs on essential residues in an oxygen-, iron-, and ␣-ketoglutarate-dependent manner. Once hydroxylated, the HIF is quickly degraded in a proteosomal-dependent process that involves the Von Hippel Lindau (VHL) tumor suppressor. HIF1␣, the most ubiquitously expressed HIF, has been shown to play a critical role in normal
Fetal Lung Liquid: A Major Determinant of the Growth and Functional Development of the Fetal Lung
Clinical and Experimental Pharmacology and Physiology, 1995
1. During fetal life the lung develops as a liquid-filled organ. This liquid is produced by the fetal lung and leaves via the trachea from where it is either swallowed or enters the amniotic sac. Fetal lung liquid plays a crucial role in the growth and development of the lungs by maintaining them in a distended state. It is now recognized that the retention of liquid within the future airways is required to maintain the lungs at an appropriate level of expansion in order to stimulate their growth. Indeed, it is likely that most, if not all, of the conditions and malformations that lead to inadequate growth of the fetal lung do so by reducing the volume of lung liquid and hence the degree of lung expansion. 2. The volume of fetal lung liquid is principally regulated by the resistance to lung liquid efflux through the fetal upper airway and by the presence of diaphragmatic activity associated with fetal breathing movements (FBM). During non-breathing periods, the relatively high resistance offered by the upper airway to the efflux of lung liquid opposes the loss of liquid from the lung, thereby maintaining fetal lung expansion. During episodes of FBM, when the larynx is actively dilated and the resistance to lung liquid efflux is reduced, lung liquid leaves the lungs at an increased rate. However, selective inhibition of diaphragmatic muscle activity in the foetus leads to a reduction in lung liquid volume, rather than an increase. This finding indicates that during periods of FBM, rhythmical contractions of the diaphragm retard the loss of lung liquid and help to maintain lung expansion when the upper airway resistance is reduced. It is now apparent that the maintenance of lung expansion by FBM is the basis for their role in promoting fetal lung growth. 3. Successful transition from intra-uterine to extra-uterine life is dependent upon the clearance of liquid from the fetal lungs at the time of birth so that the lungs may effectively function as an organ of gas exchange. It is generally considered that, at the time of birth, increased circulating levels of the stress-related hormones, adrenaline and arginine vasopressin
American journal of physiology. Lung cellular and molecular physiology, 2002
Knowledge about the conversion of the epithelium in the distal air spaces of the lung from secretion to absorption is imperative to the understanding of postnatal lung development; little such information is available in rats. Distal air space fluid clearance was therefore measured in 21- to 22-day gestation rat fetuses and newborn (40 h) rats. Distal air space fluid clearance was measured from the increase in (131)I-albumin concentration in an isosmolar, physiological solution instilled into the developing lungs. There was no net fluid movement across the distal air space epithelium in the lungs of 21-day gestation fetuses. Twenty-four hours later, distal air space fluid was cleared at a rapid rate in the 22-day gestation fetuses. Within the first 40 h after birth, the rate rapidly declined to adult levels. The high distal air space fluid clearance at 22 days gestation and at 40 h after birth was mediated by beta-adrenergic receptors as demonstrated by elevated plasma epinephrine l...
Microscopy Research and Technique, 1993
The aim of this study was to describe and compare the ultrastructural features and functional maturity of alveolar epithelial cells in hypoplastic and normal fetal rat lungs. Pulmonary hypoplasia in association with congenital diaphragmatic hernia was induced in fetuses by administration of 2,4-dichlorophenyl-p-nitrophenylether (Nitrofen) to pregnant Sprague Dawley rats (100 mg on day 10 of gestation). Lung tissue of Nitrofen-exposed and control fetal rats aged 19-22 days (vaginal plug day 1, birth day 23) was embedded in Epon. Semithin (1 km) toluidine blue-stained sections were examined by light microscopy; ultrathin sections (-80 nm) were studied via transmission electron microscopy. In bronchoalveolar lavage fluid from control and Nitrofenexposed fetuses (day 221, phospholipid fractions and surfactant protein A content were measured semiquantitatively. On day 19 both control and Nitrofen-exposed lungs contained only cuboid alveolar epithelial cells; from day 20 there were cuboid, low cuboid, and thinner epithelial cells. The (low) cuboid cells contained large glycogen fields, some precursory stages of multilamellar bodies (MLBs), and just a few mature MLBs on day 19 and 20; smaller glycogen fields, more precursory stages, and more mature MLBs on day 21; and little or no glycogen but many precursory stages and mature MLBs on day 22. The thinner cells contained little or no glycogen and a few precursory stages of MLBs on days 20-22; very thin cells on day 22 contained neither glycogen nor any precursory stages of MLBs. MLBs and tubular myelin were seen in the lumens of future air spaces from day 20 onward. Nitrofen-exposed lungs differed from control lungs in that inclusion bodies (IBs) were less numerous in (low) cuboid alveolar cells on days 19 and 20, and more glycogen was seen on day 22. In addition intra-and extracellular "MLBs" in exposed lungs more often had a n unusual appearance, i.e., a confluent structure and higher electron density. However, despite morphologic differences, there was no clear difference in phospholipid composition and SP-A content per mol phospholipid in bronchoalveolar lavage fluid. We conclude that morphologically hypoplastic lungs are less mature near term, without an apparent effect on surfactant composition. 0 1993 Wiley-Liss, Inc.
Development of human fetal lung in organ culture compared with in utero ontogeny
In Vitro Cellular & Developmental Biology - Animal, 1993
In utero, at around 23 wk gestation, the progenitor epithelium of distal airway differentiates into type I and type II pneumatocytes. Human fetal lung organ cultures, as early as 12 wk gestation, have the competence to self-differentiate. Distal airway epithelial immunoreactivity to cytokeratins CK 7, 8, and 18 decreases with differentiation both in utero and in organ culture, whereas reactivity to epithelial membrane antigen remains constant in both. As distal airways dilate, the mean percentage airspace of fetal lungs in organ culture increases to 58%, equivalent to lung of gestation 26.0 + 7.3 wk. In organ culture, capillary blood vessels, visualized by vimentin immunoreactivity, remodel and more closely approximate the epithelium but without direct invasion. In utero, at 23 wk gestation, elastin appears as condensation around airways and forms a basis for secondary crests which, by 29 wk gestation, evolve into alveolar septae. In organ culture, no elastin is deposited, no secondary or alveolar crests form, and the lung retains a simple saccular structure. Differentiation of the terminal airway epithelium and mesodermal maturational events to facilitate gas exchange, such as capillary invasion or secondary-alveolar crest formation, are almost synchronous in human lung in utero but clearly dissociate in organ culture.
American Journal of Obstetrics and Gynecology, 2001
The aim of this study was to determine the effects of intrauterine growth restriction on fetal lung liquid and lung development. STUDY DESIGN: Intrauterine growth restriction was induced in 7 fetal sheep from 120 to 140 days' gestation (term, approximately 147 days' gestation) by umbilicoplacental embolization. We used 6 control fetuses. Volumes and production rates of fetal lung liquid were measured, and lungs were removed post mortem (140 days' gestation) for analysis of concentrations of deoxyribonucleic acid, protein, and messenger ribonucleic acid for surfactant proteins A, B, and C. RESULTS: Umbilicoplacental embolization induced fetal hypoxemia, hypoglycemia, and intrauterine growth restriction. At 140 days' gestation lung weight was reduced by 34%, and the fetal lung liquid production rate (15.9 ± 1.8 mL/h for intrauterine growth restriction vs 24.8 ± 3.9 mL/h for control) and volume (110.9 ± 16.3 mL for intrauterine growth restriction vs 178.1 ± 11.9 mL for control) were reduced in the intrauterine growth restriction group. After adjustment for body weight, however, values were not different from those in the control group. Pulmonary deoxyribonucleic acid and plasma cortisol concentrations were elevated by intrauterine growth restriction, but levels of messenger ribonucleic acid for surfactant proteins were unchanged. CONCLUSION: In intrauterine growth restriction, lung liquid and lung growth were proportionate to body weight, and surfactant protein expression was unaffected. Alterations in lung deoxyribonucleic acid concentrations suggest that the lungs may be structurally immature.