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PubMed2002

Effect of intratracheal adenoviral vector administration on lung development in newborn rats.

Local overexpression of genes that promote lung defense or repair may be helpful in protecting the immature neonatal lung from injuries, but whether the vectors used to administer these genes affect physiological postnatal lung growth has not been investigated. We explored the effect on alveolarization of E1-deleted Adnull vector (Ad5-LMP-null) given intratracheally to 3-day-old rats. Three Adnull doses were evaluated 10(8), 5 x 10(8), and 10(9) TCID(50). Lung morphometry on day 21 showed significant growth disorders with the two higher doses. With 5 x 10(8) TCID(50), absolute lung volume increased significantly (+16%), as did absolute (+20%) and specific (+32%) alveolar airspace volumes, whereas alveolar surface density decreased by 13% (p < 0.009 for all parameters). Lung inflammation was mild, nonsignificant, and occurred mainly with the highest Adnull dose, indicating that it was unlikely to contribute to our results. Adnull instillation induced a significant#10; decrease in terminal bronchiolar cell proliferation as evaluated by proliferating cell nuclear antigen immunostaining (p = 0.02), as well as a 23% decrease in absolute parenchyma elastic fiber length (p = 0.02). Furthermore, lung tropoelastin mRNA content decreased by 25% (p < 0.02). In conclusion, E1-deleted adenoviral vectors can induce lung growth disorders when instilled into the airways of neonatal rats. Interactions with lung matrix turnover may be the main explanation to these deleterious effects.

Adenovirus E1A Proteins↗
PubMedDate not supplied

Cell-to-cell interactions in lung development.

A variety of cell-cell interactions, either clearly demonstrated or suspected, are associated with development of the alveolar portion of the lung. It is likely that many of these same cell-cell interactions are associated with lung maintenance in the adult and with lung repair following a variety of lung injuries.

Animals↗
PubMedDate not supplied

Induction of ICAM-1 expression on alveolar epithelial cells during lung development in rats and humans.

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion protein involved in immune and inflammatory cell recruitment and activation. In normal, uninflamed adult rat lung, ICAM-1 is expressed at high levels on type I alveolar epithelial cells and is minimally expressed on type II cells. ICAM-1 expression by alveolar epithelial cells in vitro is a function of the state of cellular differentiation, and is regulated by factors influencing cell shape. Based upon this observation, we hypothesized that ICAM-1 expression by fetal lung epithelial cells is developmentally regulated. To investigate this hypothesis, rat and human lung tissues were obtained at time points that represent the canalicular, saccular, and alveolar stages of development. The relative expression of ICAM-1 protein and mRNA were determined in rat lungs from gestational days 18 and 21 (term = 22 days), from day 8 neonatal rats, and from adult rats. ICAM-1 protein was detectable at low level on day 18 and increased progressively during development. Relative expression of ICAM-1 protein was maximal in adult lung. Expression of ICAM-1 mRNA paralleled that of ICAM-1 protein. By immunohistochemical methods in rat and human lung, ICAM-1 was expressed at low level on cuboidal and flattening epithelial cells in the developing alveolar space at the canalicular and saccular stages; however, ICAM-1 expression was increased as epithelial cells spread and flattened during alveolarization. ICAM-1 was predominantly expressed on type I cells rather than type II cells at the alveolar stage in both the rat and human lungs. Thus, relative ICAM-1 expression progressively increased during lung development. ICAM-1 expression is correlated with the increase in surface area as alveolar structures develop and type I cell differentiation takes place. These data indicate that alveolar epithelial cell ICAM-1 expression is developmentally regulated.

Adult↗
PubMed1981

Failure of C3H mice to develop lung granuloma after intravenous injection of BCG cell wall vaccine. Demonstration of a defect in lymphoid cells.

C57Bl/6 (B6) mice produced highly developed granulomata in the lung 3 or 4 weeks after intravenous injection with oil-associated BCG cell walls (CW), but C3H/He (C3H) mice did not. The potential to develop granulomata is genetically controlled (Yamamoto & Kakinuma, 1978). It is probable that the genes control only T-cell mediated granuloma and not non-specific inflammation prior to onset of immunopathological response. The retention of an FITC-labelled BCG CW preparation in the lungs of B6 and C3H mice did not differ until 10 days after injection, although 24 hr uptake of 125 I-labelled BCG CW in B6 lung was twice as much as that in C3H lung. Furthermore, C3H mice did not show a secondary type granuloma response in the lungs after subsequent injections of BCG CW. In experiments using radiation chimaeras, B6 mice reconstituted with C3H bone marrow cells were unable to produce a granulomatous response to BCG CW. In contrast, C3H mice reconstituted with B6 bone marrow cells showed a good granulomatous response. These results suggest that the C3H mice possessed a deficiency within their lympho-haematopoietic cells.

Animals↗
PubMed1990

Ductus arteriosus flow velocity modulation by fetal breathing movements as a measure of fetal lung development.

A test is needed that would accurately predict favorable neonatal lung performance in the presence of prolonged severe oligohydramnios caused by ruptured membranes so that optimal obstetric care can be provided. We propose such a test that is based on the degree of modulation of fetal ductal blood flow velocity by fetal breathing movements after maternal glucose loading. In a prospective cross-sectional study of 49 normal pregnancies (50 fetuses) between 25 and 38 weeks an exponential increase in breathing-related ductal blood flow velocity modulation was observed with advancing gestational age, reflecting the developing pulmonary vascular bed. Fetal ductal flow velocity waveforms were also recorded in 13 cases of prolonged severe oligohydramnios after ruptured membranes before 28 weeks' gestation. Normal ductal blood flow velocity modulation values were associated with normal neonatal lung performance, whereas reduced ductal blood flow velocity modulation values were associated with pulmonary hypoplasia. Fetal breathing-related ductal flow velocity modulation appears to be a promising predictor of neonatal lung performance.

Adult↗
PubMed2006

Assessment of lung development using hyperpolarized helium-3 diffusion MR imaging.

PURPOSE: To determine whether hyperpolarized helium-3 (HHe) diffusion MR can detect the expected enlargement of alveoli that occurs with lung growth during childhood. MATERIALS AND METHODS: A total of 29 normal subjects aged four to 30 years underwent HHe diffusion MR imaging with the b-value pair 0, 1.6 second/cm(2). A second acquisition during a separate breathhold was performed using the b-value pair 0, 4 second/cm(2) to evaluate the dependence on b-value. The mean apparent diffusion coefficient (ADC) and lung volume for each acquisition and each subject was determined. RESULTS: Subjects as young as four years of age were able to cooperate with the imaging procedure. The mean ADC increased with increasing subject age (r = 0.8; P < 0.001), with a 55% increase in mean ADC from the youngest to oldest subject. Lung volumes measured on MR were highly repeatable for the two HHe MR acquisitions (r = 0.980, P < 0.001). The mean ADC values measured with the two different b-value pairs were highly correlated (r = 0.975; P < 0.001), but the higher b-value pair resulted in slightly lower mean ADCs (P < 0.001). CONCLUSION: HHe diffusion MR appears to detect the expected increase in alveolar size during childhood, and thus HHe MR may be a noninvasive method to assess development of the lung microstructure.

Adolescent↗
PubMed1983

Morphology of epithelio-mesenchymal interaction during lung development of the mouse.

Basement membrane gaps and epithelio-mesenchymal contacts could be shown in the lung of mouse embryos during the entire pregnancy period. Some of the contacts corresponded to gap junctions. The significance of these findings for the differentiation of epithelium and mesenchyme, as well as for the development of the epithelial tube system of the lung as a model for the epithelio-mesenchymal interaction, has been discussed taking into account the results of other investigators. It was concluded that direct epithelio-mesenchymal contacts are necessary for organ development.

Animals↗
PubMed1993

Defects in heart and lung development in compound heterozygotes for two different targeted mutations at the N-myc locus.

Two types of mutant allele, one leaky and one null, have been generated by gene targeting at the N-myc locus in embryonic stem cells and the phenotypes of mice homozygous for these mutations have been described. These mutations have shown that N-myc has a number of functions during development, including a role in branching morphogenesis in the lung, which manifests itself at birth in mice homozygous for the leaky allele, and roles in the development of the mesonephric tubules, the neuroepithelium, the sensory ganglia, the gut and the heart, which become evident at midgestation in embryos homozygous for the null allele. In an attempt to define roles for N-myc at other stages of development, we have combined the two types of N-myc mutant allele in a compound heterozygote that as a result contains approximately 15% of normal levels of N-Myc protein. Compound heterozygotes died during gestation at a time intermediate to the times of death of embryos homozygous for either mutation individually, and their death appeared to result from cardiac failure stemming from hypoplasia of the compact subepicardial layer of the myocardium. Investigation of the expression pattern of N-myc and various markers of differentiation in wild-type and compound heterozygote mutant hearts has suggested that N-myc may function in maintaining the proliferation and/or preventing the differentiation of compact layer myocytes. This study illustrates the importance of generating different mutations at a given locus to elucidate fully the function of a particular gene during development.

Animals↗
PubMed1998

Morphometric analysis of postnatal lung development in the tammar wallaby: light microscopy.

Postnatal growth of the lung in the tammar wallaby, Macropus eugenii, was investigated using morphometric techniques with light microscopy. Lung volume, parenchymal and non-parenchymal volume densities were measured. Volume densities of parenchymal airspace and tissue and non-parenchymal conducting airways and large blood vessels were determined. Lung volume and all the other parameters that were measured showed a biphasic increase in relation to increase in body mass. All parameters, with the exception of airway volume, increased relatively slowly in relation to increase in mass in the first 70 days after birth, when the pouch young are ectothermic. Between 70 and 180 days, during the period of transition from ectothermy to endothermy, the parameters increased more rapidly, suggesting accelerated lung growth in preparation for the extra metabolic demands associated with the establishment of thermoregulatory control in the pouch young. Specific lung volume in the adult tammar is lower than that of eutherians of equivalent mass, however, the parenchymal volume is relatively high.

Aging↗
PubMed2005

Expression of glucocorticoid, retinoid, and thyroid hormone receptors during human lung development.

CONTEXT: Although glucocorticoid hormone, thyroid hormone, and retinoic acid play important roles in fetal development, the expression of their receptors in human lung is still unknown. OBJECTIVE: The aim of this study was to investigate the ontogeny of glucocorticoid receptor (GR)alpha, thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and retinoid X receptors (RXRs) mRNA expression in human lungs. DESIGN: Lungs from human fetuses and neonates (13.5-41 wk gestation; n = 20) as well as adults (n = 5) were analyzed by real-time PCR to monitor the ontogeny of mRNA expression for each receptor. In addition, immunohistochemistry was performed to show the cellular distribution of the different receptors. RESULTS: The expression of GRalpha, TRs, RARs, and RXRs was already detected in the earliest developmental stages analyzed. There was no significant difference in mRNA expression between developmental groups for any of the genes studied. However, for fetal and neonatal samples, there were positive correlations between gestational age and mRNA expression for RARalpha (r = 0.665; P = 0.001), RXRalpha (r = 0.444; P = 0.050), and RXRgamma (r = 0.464; P = 0.039). Immunohistochemical studies showed the presence of GRalpha, TRs, RARs, and RXRs in the nuclei of both epithelial and mesenchymal cells, albeit more pronounced in epithelium of larger airways. CONCLUSIONS: The detection of GRalpha, TRs, RARs, and RXRs expression in human lung as early as 13.5 wk gestation implies an early potential for therapeutic or toxic effects by exogenous analogs or by excess of endogenous ligands.

Female↗
PubMed1985

Fetal lung development in the diabetic pregnancy.

It seems quite likely that the normal process of fetal lung biochemical maturation is delayed by maternal diabetes and that abnormalities in the pulmonary surfactant system are involved. The appearance of PG in amniotic fluid and possibly in fetal lung is impaired or at least delayed. The same is possibly true for DSPC, the main constituent of surfactant, but recent discrepant data call for further clarification of this specific point. Careful determination of the fetal lung phospholipid profile by amniotic fluid analysis helps predict and prevent RDS in IDM, along with a careful control of the maternal diabetic condition. A study of alveolar surfactant at birth, if it could be performed in addition to amniotic fluid analysis, would help to better characterize surfactant deficiency in IDM. On the basis of both in vivo and in vitro experimental approaches, it seems clear that hyperglycemia and fetal reactional hyperinsulinism are both involved in the processes delaying fetal lung maturation. Further advances in the understanding of cellular and molecular mechanisms leading to this delay will be conditional on the availability of animal models reproducing the features of the metabolic and hormonal environment of human fetuses in diabetic pregnancies. The appropriateness of in vivo models needs to be defined by two kinds of criteria: 1) presence of simultaneous hyperglycemia and hyperinsulinemia in the fetus; 2) the presence of delayed fetal lung maturation as judged by morphology and morphometry of epithelial lung cells, by physiological assessment of surfactant, and by the phospholipid composition of the lung (and including lung tissue per se, bronchoalveolar lavage fluid, lamellar bodies, and/or isolated surfactant fractions). Therefore, future studies must necessarily be comprehensive in scope and include information indicating that fetal growth, blood glucose, and circulating insulin are all increased. Such models already exist in rats and rabbits. Rat models are possibly not the best because of the high basal level of fetal blood insulin in this species and the relatively rapid rate of lung maturation that is not analogous to the human. Monkey models are of interest, because of their close relationship with the human pregnancy, and need to be studied further. They are particularly attractive also because primary fetal hyperinsulinism can be studied (268), as well as the combination of hyperglycemia and hyperinsulinemia in pregnancies of STZ-treated monkeys (152). An appropriate model of the diabetic pregnancy could provide answers to the following questions. Are the biosynthetic pathways of surfactant phospholipids directly impaired?(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Collagen synthesis during lung development and during hyaline membrane disease in the nonhuman primate.

To assess maturational changes in collagen synthesis, lung tissue was obtained from healthy Macaca nemestrina monkeys at different ages, ranging from 68% of term gestation to adulthood. We hypothesized that infants delivered prematurely have a greater rate of collagen synthesis than do older animals because of their greater rate of lung growth during gestation. Secondly, we hypothesized that lung repair in infants with hyaline membrane disease (HMD) is associated with an additional increase in lung collagen synthesis rate. Therefore, lung tissue was obtained during the first week of life from monkeys delivered at 82% of term gestation, a stage at which half of them developed HMD. The rate of total protein synthesis in lung samples was determined by measuring the incorporation of [3H]proline; the rate of collagen synthesis was determined by measuring the conversion of proline into hydroxyproline. Premature monkeys had a higher rate of collagen synthesis (9.9 +/- 2.7 nmol/mg DNA/h) than did term infants (5.3 +/- 1.1) or older animals (2.1 +/- 0.4, p less than 0.05). There was no additional increase in rate of collagen synthesis in animals with HMD from 3 h (14.3 +/- 6.9) to 7 days of age (15.1 +/- 6.1); control premature animals also had no significant change during the first week of life (10.9 +/- 3.0 at 3 h; 11.6 +/- 4.6 at 7 days). The early stage of recovery from HMD in premature monkeys does not appear to be associated with an increase in collagen production beyond the already increased synthesis rate associated with lung growth.

Analysis of Variance↗
PubMed2006

Igf2 deficiency results in delayed lung development at the end of gestation.

IGF-II is a polypeptide hormone with structural homology to insulin and IGF-I. IGF-II plays an important role in fetal growth as mice with targeted disruption of the IGF-II gene (Igf2) exhibit severe growth retardation. The role of IGFs in the fetal lung has been suggested by several studies, including those that have identified IGF mRNA expression, and that of their receptors and binding proteins in the lungs at different stages of development. In this study, we used mice carrying a null mutation of Igf2 (Igf2-/- mice) to determine whether the absence of IGF-II had any effect in fetal lung maturation. Our results showed that the lungs of Igf2-/- fetuses had thicker alveolar septae and poorly organized alveoli when compared with those of Igf2+/+ on d 17.5 and 18.5 of gestation. These morphological alterations may be the result of exposure to lower levels of glucocorticoids because plasma corticosterone levels were significantly lower in Igf2-/- mothers compared with wild-type controls. In support of this, fetuses from homozygous knockout matings, where mothers were treated with 15 microg/ml corticosterone, and Igf2-/- fetuses obtained from heterozygous matings had similar lung histology to those of wild-type fetuses. Finally, we found that IGF-I and SP-B mRNA levels were up-regulated in the lungs of Igf2-/- fetuses at the end of gestation. This study suggests that Igf2 plays an important role in the development of the fetal lung and may affect fetal lung maturation by regulating maternal factors, such as corticosterone levels, during pregnancy.

Animals↗
PubMed2001

Respiratory mechanics and lung development in the rat from early age to adulthood.

The purpose of the present study was to establish how the dependence of respiratory mechanics on lung inflation changes during development. We studied seven groups of rats from 10 days to 3 mo of age at five levels of positive end-expiratory pressure (PEEP) from 0 to 7 hPa (1 hPa = 0.1 kPa approximately 1 cmH(2)O). At each PEEP level, we measured respiratory system resistance and elastance at both 0.9 and 4.8 Hz to partition the mechanical properties into its airway and tissue components. Elastance increased more rapidly with PEEP in the younger animals, which we interpret as reflecting a more pronounced strain stiffening of the younger parenchyma. However, the decrease in airway resistance with PEEP was more pronounced in the older animals. Morphometric analysis showed that mean tissue density decreased and total alveolar surface area increased with age. Our data suggest that the mechanical interdependence between airways and parenchyma is weaker in very young animals compared with mature animals. This may play a role in the hyperresponsiveness of immaturity.

Aging↗
PubMed1984

Influence of maternal diabetes on basement membranes, type 2 cells, and capillaries in the developing rat lung.

To determine the effect of maternal diabetes on rat lung development, we studied the ultrastructure of the alveolar wall from the ninteenth day of gestation (term = 22 days) through the eighth postnatal day in fetal and neonatal rats of mothers with streptozotocin-induced diabetes. In normal fetal lung development, epithelial basement membranes develop large discontinuities beneath type 2 cells, through which cytoplasmic foot processes extend into the interstitium. Maternal diabetes delays the appearances of these epithelial basement membrane discontinuities and reduces the number of type 2 cell processes that penetrate it. These alterations in epithelial basement membrane are reversed after birth. There is no ultrastructural evidence of a delay in type 2 cell maturation as assessed by lamellar body volume density morphometry. Endothelial basement membranes, which are not present around the growing pulmonary capillary bed in the pseudoglandular lung, are seen late in normal gestation, primarily around capillaries forming the mature air-blood barrier. This development of endothelial basement membrane may be delayed in the fetuses of diabetic mothers and reflects a significant delay in the expansion of the pulmonary capillary network in these animals as assessed by morphometric volume density measurements. This effect on capillary growth is not reversed in the newborn animals through 8 days after birth. The summation of these effects indicates a generalized slowing of fetal lung development by maternal diabetes, some of which effects persist after birth and may continue to influence lung development during the period of postnatal alveolar septal growth.

Animals↗
PubMed2003

Morphometry and allometry of the postnatal marsupial lung development: an ultrastructural study.

An utrastructural morphometric study of the postnatally remodelling lungs of the quokka wallaby (Setonix brachyurus) was undertaken. Allometric scaling of the volumes of the parenchymal components against body mass was performed. Most parameters showed a positive correlation with body mass in all the developmental stages, except the volume of type II pneumocytes during the alveolar stage. The interstitial tissue and type II cell volumes increased slightly faster than body mass in the saccular stage, their growth rates declining in the alveolar stage. Conversely, type I pneumocyte volumes increased markedly in both the saccular and alveolar stages. Both capillary and endothelial volumes as well as the capillary and airspace surface areas showed highest rates of increase during the alveolar stage, at which time the rate was notably higher than that of the body mass. The pulmonary diffusion capacity increased gradually, the rate being highest in the alveolar stage and the adult values attained were comparable to those of eutherians.

Aging↗