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PubMed1981

The effect of bilateral thoracoplasty on lung development in fetal sheep.

The relationship of breathing movements to lung development in the ovine fetus was investigated by partially removing ribs on each side of the chest and closing the deficiencies with silicone membranes at 114 days of gestation; the increase in compliance of the chest wall that resulted caused blunting of the amplitude of phasic negative pressures recorded in the trachea to less than 10 torr. Compared to sham operated controls (n = 5), the lungs of the thoracoplasty group (n = 5) at term weighed significantly (P less than 0.05) less, both wet (1.5 +/- 0.2 v. 2.3 +/- 0.1% of body weight) and dry (0.14 +/- 0.01 v. 0.18 +/- 0.01% of body weight. In addition, DNA content of the thoracoplasty group was less than that of the control group (0.47 +/- 0.05 mg v. 0.72 +/- 0.20 mg). Distensibility of the left lung with air at 40 cmH20 was less than in the thoracoplasty group than in controls (10.0 +/- 2.0 v. 18.9 +/- 3.0 ml.kg-1 body weight) but no differences were found in the concentrations of saturated phosphatidylcholine in lung tissue and lavage fluid, in DNA concentrations or in the amount of lung water (as % of wet weight of lung). It is concluded that phasic negative pressures of normal intensity are necessary for normal development of the fetal lungs.

Animals↗
PubMed2006

Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema.

Cigarette smoking is the strongest risk factor for emphysema. However, sensitivity to cigarette smoke-induced emphysema is highly variable, and numerous genetic and environmental factors are thought to mitigate lung response to injury. We report that the quantity of functional elastin in the lung is an important modifier of both lung development and response to injury. In mice with low levels of elastin, lung development is adversely affected, and mice manifest with congenital emphysema. Animals with intermediate elastin levels exhibit normal alveolar structure but develop worse emphysema than normal mice following cigarette smoke exposure. Mechanical testing demonstrates that lungs with low levels of elastin experience greater tissue strains for any given tissue stress compared with wild-type lungs, implying that force-mediated propagation of lung injury through alveolar wall failure may worsen the emphysema after an initial enzymatic insult. Our findings suggest that quantitative deficiencies in elastin predispose to smoke-induce emphysema in animal models and suggest that humans with altered levels of functional elastin could have relatively normal lung function while being more susceptible to smoke-induced lung injury.

Animals↗
PubMed1993

Cystic fibrosis gene and protein expression during fetal lung development.

The cystic fibrosis transmembrane conductance regulator (CFTR) transports Cl- in the apical membrane of secretory epithelial cells. Normal lung development is critically dependent on active Cl- secretion by developing airway epithelia. In this study, the polymerase chain reaction (PCR) was used to detect CFTR mRNA expression in rabbit lung at different stages of development. Using nested amplification in exons 7 and 11, a 494-bp fragment was isolated from cDNA prepared from lungs obtained at gestational days 22 (pseudoglandular) and 29 (terminal sac). Nucleotide sequencing verified the identification of rabbit CFTR sequences. At day 22 of gestation, CFTR was detected in fetal liver, kidney, heart, intestine, and brain. CFTR could not be amplified from adult rabbit brain. CFTR protein was detected using a polyclonal antibody raised in chickens against a synthetic peptide from the R domain conjugated to thyroglobulin. Rabbit CFTR migrated as a 165-kD protein on 5% sodium dodecyl sulfate polyacrylamide gels when detected either by chicken anti-R IgG or a previously characterized rabbit anti-R antibody. In frozen sections of fetal rabbit lung at day 22 of gestation, CFTR was localized to the membrane regions of primitive tubular epithelial cells and absent from surrounding connective tissue. At day 29, CFTR was concentrated in the apical region of bronchiolar epithelial cells and absent from alveoli and vessels. These results suggest that CFTR gene expression begins very early in lung development and, with differentiation of the airways, becomes confined to differentiated bronchiolar epithelium, the presumed site for cAMP-mediated Cl- secretion.

Amino Acid Sequence↗
PubMed1983

Effect of tracheostomy on lung development in fetal lambs.

The effects of fetal tracheostomy on lung development in lambs have been investigated. Seven ewes, all with twin fetuses, were given a general anesthetic. One fetus in each set of twins was tracheostomized and the other fetus was sham operated (117-122 days gestation). The fetuses were delivered by cesarean section between 137 and 140 days gestation. Fetal tracheostomy decreased lung weight and volume, altered DNA concentration and the structural development of the acinus, and decreased lung distensibility. However, tissue and airway saturated phosphatidylcholine and lung stability during deflation were not significantly affected by fetal tracheostomy. It seems that tracheostomy in fetal lambs alters lung growth but does not affect the formation or release of surfactant. These data support the hypothesis that lung volume is actively maintained and lung growth promoted by the secretion of lung fluid against the resistance of the upper airway in fetal lambs.

Animals↗
PubMed2004

Assessment of fetal lung development by quantitative ultrasonic tissue characterization: a methodical study.

OBJECTIVES: This study was performed to evaluate the quantitative ultrasonic tissue characterization of the normal fetal lung development by using acoustic raw data captured after preprocessing. METHODS: One hundred and sixty-two patients with completed gestational ages between 22 and 37 weeks were enrolled in this study. Longitudinal and transverse sections of the fetal thorax and upper abdomen were imaged. A region of interest of constant size was defined and the tissue-specific gray scale was determined by using an interactive software. RESULTS: A total of 162 patients met the inclusion criteria. The echogenicity of the fetal lung showed a particular changing pattern during pregnancy: the mean gray value of the fetal lung (MGV) is almost the same as the MGV of the fetal liver at 22 and 23 weeks, decreases between 22 and 31 weeks and increases between 31 and 37 weeks. The MGV of the fetal liver decreases significantly from 24 weeks to 31 weeks and increases significantly again toward 37 weeks. We stated that the MGV of the lung is smaller than the MGV of the liver during 31 weeks of gestation and the relation reverses in late gestation. At term, the MGV of the liver is greater than the MGV of the lung. The lung-to-liver ratio is <1 between 24 and 29 weeks and >1 between 30 and 35 weeks. CONCLUSION: The echogenicity of the fetal lung showed a particular changing pattern during pregnancy, which corresponds to morphologic changes of the fetal lung development.

Female↗
PubMed1993

Prenatal evaluation and obstetrical management of fetuses at risk of developing lung hypoplasia.

The aim of this study was to measure the fetal lung area of normal human fetuses using ultrasound and them to test the predictive values of a nomogram in the identification of fetal lung hypoplasia. A nomogram for ultrasound-measured fetal lung area were constructed from 264 normal fetuses from 17 to 39 weeks of gestation. In 19 cases running the risk of developing lung hypoplasia, the sensitivity, specificity, and positive and negative predictive values of lung area measurements below the mean -2 SD were 75%, 100%, 94% and 100%, respectively, with total lung area showing a significant relation to the combined lung weight (Y = -1.05 + 2.06 X, r2 = 0.88). These results indicate that lung area measured by ultrasound is a good indicator of lung weight, and this nomogram of lung area may be useful in evaluating lung growth prenatally, as well as in the direct obstetrical management of fetuses at risk of developing lung hypoplasia.

Female↗
PubMed2007

Maternally imprinted microRNAs are differentially expressed during mouse and human lung development.

MicroRNAs (miRNAs) are a recently discovered class of noncoding genes that regulate the translation of target mRNA. More than 300 miRNAs have now been discovered in humans, although the function of most is still unknown. A highly sensitive, semiquantitative real-time polymerase chain reaction method was used to reveal the differential expression of several miRNAs during the development of both mouse and human lung. Of note was the up-regulation in neonatal mouse and fetal human lung of a maternally imprinted miRNA cluster located at human chromosome 14q32.31 (mouse chromosome 12F2), which includes the miR-154 and miR-335 families and is situated within the Gtl2-Dio3 domain. Conversely, several miRNAs were up-regulated in adult compared with neonatal/fetal lung, including miR-29a and miR-29b. Differences in the spatial expression patterns of miR-154, miR-29a, and miR-26a was demonstrated using in situ hybridization of mouse neonatal and adult tissue using miRNA-specific locked nucleic acid (LNA) probes. Of interest, miR-154 appeared to be localized to the stroma of fetal but not adult lungs. The overall expression profile was similar for mouse and human tissue, suggesting evolutionary conservation of miRNA expression during lung development and demonstrating the importance of maternally imprinted miRNAs in the developmental process.

Animals↗
PubMed2003

Hypoxia and Rho/Rho-kinase signaling. Lung development versus hypoxic pulmonary hypertension.

Intracellular signaling via the small GTP-binding protein RhoA and its downstream effector Rho-kinase plays a role in regulating diverse cellular functions, including cell contraction, migration, gene expression, proliferation, and differentiation. Rho/Rho-kinase signaling has an obligatory role in embryonic cardiac development, and low-level chemical activation of Rho promotes branching morphogenesis in fetal lung explants. Gebb has found that hypoxia markedly augments branching morphogenesis in fetal rat lung explants, and our preliminary results suggest this is associated with activation of RhoA. Whereas hypoxia-induced activation of Rho/Rho-kinase may promote fetal lung development, other evidence indicates it has adverse effects in the lungs of neonates and adults. When exposed at birth to the mild hypoxia of Denver's altitude (5,280 ft), the neonatal fawn-hooded rat (FHR) develops severe pulmonary hypertension (PH) associated with impaired lung alveolarization and vascularization. We have observed that administration via the drinking water of the Rho-kinase inhibitor fasudil to the nursing, Denver FHR mother for the first 2 to 3 weeks, and then directly to the Denver FHR pups for the next 7 to 8 weeks, ameliorates the lung dysplasia and PH. The adult Sprague-Dawley rat develops PH when exposed for 3 to 4 wk to a simulated altitude of 17,000 ft. We have found that this hypoxic PH is associated with activation of pulmonary artery Rho/Rho-kinase and is almost completely reversed by acute intravenous administration of the Rho-kinase inhibitor Y-27632. In addition, chronic in vivo treatment with Y-27632 reduces development of the hypoxic PH. In summary, hypoxic activation of Rho/Rho-kinase signaling may be important for fetal lung morphogenesis, but continued activation of this pathway in the neonate impairs postnatal lung development and re-activation in the adult contributes to development of PH.

Altitude↗
PubMed1995

Effect of indomethacin on lung development in postnatal rats: possible role of prostaglandin in alveolar formation.

We administered 1.3 mg ip of indomethacin, a prostaglandin synthetase inhibitor, per 100 g body wt to male rat pups daily on postnatal days 4-13 and examined their lungs on day 14. Indomethacin administration produced abnormal lung structure with diminished alveolar air, increased alveolar duct air, increased mean linear intercept (gas-exchanging wall distance), diminished gas-exchanging surface area and surface-to-volume ratio, increased septal wall thickness, diminished the number of alveolar crests, and increased the number of lamellar bodies in alveolar type II cells. However, this procedure did not alter quantitative lung growth (normal lung weights, volumes, and DNA and protein contents). Tissue prostaglandin content was decreased. The total amount of lung collagen or elastin was unchanged, but when collagen was analyzed into soluble and insoluble components, soluble collagen was increased. Supplementation with 1.0 g of prostaglandin E2 per 100 g body wt to animals treated with indomethacin reduced the abnormalities in pulmonary architecture. We conclude that indomethacin affects lung structure in growing rats and that it is an unusual model in that lung growth is normal, but lung development is abnormal. We also suggest that prostaglandins may play a significant role in alveolar formation in postnatal lung development in rats.

Animals↗
PubMed1983

Elastin synthesis during perinatal lung development in the rat.

The rate of soluble elastin synthesis was estimated in lung explants from rats of differing ages to better define periods in lung development important to the deposition of lung elastin. Lungs from rat pups at days 1, 3, 7, 9, 12, 15, and 21 post-parturition and from adult rats were incubated in a defined medium containing L-[3H]valine. Following incubation, labelled soluble elastin (tropoelastin) was separated from other soluble proteins by coacervation and electrophoresis on polyacrylamide gels containing sodium dodecyl sulfate. The tropoelastin synthetic rate was then estimated after correcting for differences in recovery of radioactivity as tropoelastin and lung tissue L-[3H]valine specific activity. Maximal rates of elastin synthesis were observed in lung explants from 7-12-day-old rats. The rate of elastin synthesis during this period was 5-8-times the rate observed in adult rat lung (expressed per g of fresh lung) and represented approx. 2% of the total protein synthesis. Moreover, the values derived from lung explant culture for elastin synthesis were consistent with values for lung elastin deposition in the perinatal rat (5-10 micrograms elastin/h per g lung).

Aging↗
PubMed2001

Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis.

BACKGROUND: Previously, we reported that Sema3A, one of the secreted repulsive axon guidance molecules, CRMP (collapsin response mediator protein)-2, a putative intracellular signalling molecule for Sema3A and Sema3A receptor neuropilin-1 are expressed in the developing lung. Sema3A inhibits branching morphogenesis of embryonic lung in organ culture. RESULTS: We examined the gene expression of Sema3A, Sema3C, Sema3F and their receptors, NP-1, NP-2 and plexin-A1 by in situ hybridization. Transcripts of all six genes were detected in mouse lung from embryonic day E11.5 to E17.5, and displayed highly specific spatiotemporal distributions. The distribution of the receptor genes was detected in patterns which were consistent with known receptor usage of the semaphorins. In contrast to Sema3A, we found that the other class 3 semaphorins, Sema3C and Sema3F, stimulated branching morphogenesis. This stimulatory effect of Sema3C or Sema3F was accompanied by a moderate increase in the incorporation of bromodeoxyuridine (BrdU) into DNA in the terminal epithelial cells. CONCLUSION: The coordinated expression patterns of different semaphorins and their receptors, together with the specific activities affecting branching morphogenesis, suggest that the semaphorins act as both positive and negative regulators of branching morphogenesis in the developing lung.

Animals↗
PubMed2005

Distribution of ERK1/2 and ERK3 during normal rat fetal lung development.

The extracellular regulated kinases-1 and -2 (ERK1/2) are well-characterized mitogen-activated protein kinases (MAPK) that play critical roles in proliferation and differentiation, whereas the function(s) of MAPK ERK3 are currently unknown. To understand better the roles of these kinases in development, the temporal distribution of ERK1, -2, and -3 proteins were investigated in multiple tissues. The ERK3 protein, in contrast to ERK1/2 varied both between and within individual organs over time. To characterize this variability in greater detail, the temporal and spatial distributions of activated ERK1/2 and ERK3 during rat fetal lung development were investigated. The diphosphorylated (activated) forms of ERK1/2 (dp-ERK1/2), ERK3, and its phosphorylated form (P-ERK3) decreased from embryonic day 17 (E17) through E21 while both ERK1 and ERK2 total proteins remained unchanged, indicating that ERK1/2 and ERK3 proteins are expressed independently during fetal lung development. In addition, characterization of the distribution of these proteins by fluorescent immunohistochemistry indicated that phosphorylated ERK1/2 and total ERK1/2 were distributed throughout multiple cell types, with the phosphorylated ERK1/2 colocalizing with prophase mitotic cells. In contrast, ERK3 was restricted to the distal lung epithelium during the pseudoglandular phase (E17) but shifted to the proximal airways, particularly Clara cells during the saccular stage (E21). The P-ERK3 colocalized with the mitotic marker P-histone H3 in fetal lung and in NIH3T3 and HeLa cells, implicating a potential role for P-ERK3 in mitosis. Thus, expression of ERK1/2 and ERK3 and their phosphorylated forms are expressed independently and are temporally and spatially localized during fetal lung morphogenesis. These observations will facilitate detailed functional analysis of these kinases to assess their roles in pulmonary development and diseases.

Animals↗
PubMed2001

Glucocorticoids and lung development in the fetus and preterm infant.

During the final prenatal period of fetal lung development in humans, important maturational processes occur, including the production of surfactant necessary to decrease surface tension at the air-liquid interface of the alveoli. During early gestation, the glucocorticoid receptor is expressed in the fetal lung, and glucocorticoids stimulate the production of surfactant-associated proteins and increase phospholipid synthesis by enhancing the activity of phosphatidylcholine. Other glucocorticoid-induced effects may include stimulation of cell maturation and differentiation, inhibition of DNA synthesis, changes in interstitial tissue components, stimulation of antioxidant enzymes, and regulation of pulmonary fluid metabolism. Recently, it was suggested that glucocorticoids are also important in postnatal pulmonary development, and may be related to the development of neonatal lung disease in preterm infants. Surfactant deficiency that can be prevented by antenatal corticosteroid treatment causes infant respiratory distress syndrome and requires mechanical ventilation. Ventilation by itself or in combination with high levels of oxygen, fluid overload, pulmonary infections, sepsis, and air leak syndrome causes an acute pulmonary inflammatory reaction that may result in chronic lung disease or bronchopulmonary dysplasia. Glucocorticoids are effective in the treatment of chronic lung disease of prematurity and regulate the inflammatory response by the interaction with transcription factors such as nuclear factor kappaB and activated protein 1. Indeed, inflammatory cells and the levels of chemokines and cytokines in bronchoalveolar fluid decrease after dexamethasone treatment. However, treatment of fetuses and preterm infants with repeated and/or high doses of corticosteroids may have considerable long-term side effects on somatic, brain, and lung growth. The difficult balance between short-term gain and the possible long-term side effects of glucocorticoids in preterms remains a difficult issue.

Female↗
PubMed1981

The effect of spinal cord transection on lung development in fetal sheep.

The relationship of breathing movements to lung development in the ovine fetus was investigated by transecting the fetal cervical spinal cord above (C2-C3; n = 4) or below (C7-C8; n = 4) the phrenic nucleus at 114 days of gestation. The fetuses were delivered by hysterotomy at term and compared with a group of intact term fetuses (n = 8). Cord transection at C2-C3 resulted in a significant (P less than 0.05) reduction in wet weight of the lungs to 1.56 +/- 0.23% of body weight from 2.59 +/- 0.83% in the C7-C8 group. The diaphragms of the two groups did not differ in weight or histological appearance. Distensibility of the left lung with air at 40 cmH20 was significantly less in the C2-C3 group (6.8 +/- 3.5 ml.kg-1 body weight) than the C7-C8 group (19.9 +/- 3.7 ml.kg-1) or the intact controls (15.2 +/- 5.4 ml.kg-1). DNA content in the C2-C3 group (0.63 +/- 0.12 g) was less than in controls (0.99 +/- 0.19 g) but it was not different from the C7-C8 group (0.82 +/- 0.33 g.) DNA concentration, water content and saturated phosphatidylcholine concentration in lung tissue and lavage fluid were similar in the three groups. It is concluded that the absence of breathing movements caused by transection of the spinal cord above the phrenic nucleus is associated with retarded lung growth and maturation.

Animals↗
PubMed2002

Distribution of laminin 5, integrin receptors, and branching morphogenesis during human fetal lung development.

The role of the epithelial adhesion ligand laminin 5 (LN5) in lung development has been poorly investigated. To determine its potential involvement in lung organogenesis, we used immunofluorescence microscopy to investigate the distribution of LN5 and its integrin (Int) receptors alpha2beta1, alpha3beta1, alpha6beta1, and alpha6beta4 during human fetal airway branching morphogenesis and respiratory epithelium differentiation. At the pseudoglandular and canalicular stages of airway development, LN5 and its constituent chains were localized in the basement membrane (BM) of the proximal respiratory tubules and in the cytoplasm of the epithelial cells forming the growing epithelial buds, which expressed Int alpha2beta1, alpha3beta1, and, transiently, alpha6beta1. At the alveolar and adult stages, LN5 and its constituent chains were localized both in the BM of evolving and differentiated bronchioles and in the alveolar parenchyma. The bronchiolar epithelium markedly expressed Int alpha2beta1 and alpha3beta1, whereas the alveolar parenchyma strongly expressed Int alpha2beta1, alpha3beta1, and alpha6beta1. Throughout fetal development and in the adult, LN5 and its constituent chains were detected both in the tracheal BM, regardless of the degree of epithelial differentiation, and in the cytoplasm of the cells at the invading front of the growing glandular ducts. Ultrastructural studies showed that nucleation of the hemidesmosomes (HDs) correlated with the differentiation of the tracheal epithelium. These results suggest that LN5 may play multiple roles during branching morphogenesis, by modulating proliferation and/or migration of the epithelial cells in the respiratory buds and by establishing branch points, through interaction initially with Int alpha6beta1 and later with Int alpha2beta1 and alpha3beta1. We also propose that LN5 may regulate the differentiation of the tracheal epithelium by means of Int-beta4, which governs HD nucleation.

Cell Differentiation↗