The effect of maternal exercise on somatic growth and lung development of fetal rats: Morphologic and morphometric studies

Allan, Douglas W., and John J. Greer. Pathogenesis of nitrofen-induced congenital diaphragmatic hernia in fetal rats. J. Appl. Physiol. 83(2): 338–347, 1997.—Congenital diaphragmatic hernia (CDH) is a developmental anomaly characterized by the malformation of the diaphragm and impaired lung development. In the present study, we tested several hypotheses regarding the pathogenesis of CDH, including those suggesting that the primary defect is due to abnormal 1) lung development, 2) phrenic nerve formation, 3) developmental processes underlying diaphragmatic myotube formation, 4) pleuroperitoneal canal closure, or 5) formation of the primordial diaphragm within the pleuroperitoneal fold. The 2,4-dichloro-phenyl- p-nitrophenyl ether (nitrofen)-induced CDH rat model was used for this study. The following parameters were compared between normal and herniated fetal rats at various stages of development: 1) weight, protein, and DNA content of lungs; 2) phrenic nerve diameter, axonal number, and motoneuron distribution; 3) formation of the phrenic nerve intramuscular branching pattern and diaphragmatic myotube formation; and 4) formation of the precursor of the diaphragmatic musculature, the pleuroperitoneal fold. We demonstrated that previously proposed theories regarding the primary role of the lung, phrenic nerve, myotube formation, and the closure of pleuroperitoneal canal in the pathogenesis of CDH are incorrect. Rather, the primary defect associated with CDH, at least in the nitrofen rat model, occurs at the earliest stage of diaphragm development, the formation of the pleuroperitoneal fold.

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Impaired somatic growth and delayed lung development in infants with congenital diaphragmatic hernia—evidence from a 10-year, single center prospective follow-up study

Journal of Pediatric Surgery ◽

10.1016/j.jpedsurg.2008.10.047 ◽

2009 ◽

Vol 44 (7) ◽

pp. 1309-1314 ◽

Cited By ~ 17

Author(s):

Charles Christoph Roehr ◽

Hans Proquitté ◽

Andreas Jung ◽

Ulrike Ackert ◽

Christian Bamberg ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Lung Development ◽

Somatic Growth ◽

Single Center ◽

Follow Up Study

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Exercise during pregnancy and maternal and fetal plasma corticosterone and androstenedione in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.5.e896 ◽

1996 ◽

Vol 271 (5) ◽

pp. E896-E902 ◽

Cited By ~ 5

Author(s):

K. A. Carlberg ◽

B. L. Alvin ◽

A. R. Gwosdow

Keyword(s):

Maternal Blood ◽

Plasma Corticosterone ◽

Blood Collection ◽

Fetal Blood ◽

Sprague Dawley ◽

Fetal Plasma ◽

Fetal Blood Sampling ◽

Sprague Dawley Rats ◽

Fetal Rats ◽

Maternal Exercise

Adrenocortical glucocorticoid and androgen secretion is stimulated by exercise. Excesses of these hormones in fetuses can cause abnormalities in development. We measured maternal and fetal plasma corticosterone and androstenedione concentrations in Sprague-Dawley rats immediately after maternal exercise in exercise-trained mothers and at rest in sedentary mothers. To do this, we developed a technique for fetal blood sampling and assessed its effect on maternal and fetal plasma corticosterone concentrations. Under halothane anesthesia, maternal blood was collected by cardiac puncture and fetal blood was collected from carotid and jugular vessels. Corticosterone was not affected by the blood collection procedure. Corticosterone was significantly higher in exercised mothers and their fetuses after 30 min of running than in sedentary mothers and their fetuses at rest. Androstenedione was significantly higher in exercised mothers after 30 min of running than in sedentary mothers at rest, but fetal androstenedione was not different between groups. We conclude that this maternal exercise protocol elevates plasma corticosterone but not androstenedione concentrations in fetal rats.

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TGF-β-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00389.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L151-L161 ◽

Cited By ~ 102

Author(s):

Hidehiko Nakanishi ◽

Takahiro Sugiura ◽

James B. Streisand ◽

Scott M. Lonning ◽

Jesse D. Roberts

Keyword(s):

Lung Development ◽

Neutralizing Antibodies ◽

Transforming Growth Factor ◽

Pulmonary Inflammation ◽

Somatic Growth ◽

Pulmonary Injury ◽

Matrix Assembly ◽

Terminal Stage ◽

Important Regulator

Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. Transforming growth factor (TGF)-β is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF-β in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF-β in the inhibition of the terminal stage of lung development is incompletely understood. In this investigation, the hypothesis that O2-induced injury of the maturing lung is associated with TGF-β-mediated disruption of alveologenesis and microvascular development was tested using a murine model of BPD. Here we report that treatment of developing mouse lungs with TGF-β-neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF-β signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF-β activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF-β antibodies is associated with improved somatic growth in hyperoxic mouse pups and not with an increase in pulmonary inflammation. These studies indicate that excessive pulmonary TGF-β signaling in the injured newborn lung has an important role in the disruption of the terminal stage of lung development. In addition, they suggest that anti-TGF-β antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung.

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Soluble guanylate cyclase modulates alveolarization in the newborn lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00401.2012 ◽

2013 ◽

Vol 305 (8) ◽

pp. L569-L581 ◽

Cited By ~ 21

Author(s):

Patricia R. Bachiller ◽

Katherine H. Cornog ◽

Rina Kato ◽

Emmanuel S. Buys ◽

Jesse D. Roberts

Keyword(s):

Guanylate Cyclase ◽

Lung Development ◽

Soluble Guanylate Cyclase ◽

Somatic Growth ◽

Wild Type ◽

Body Weights ◽

Mean Linear Intercept ◽

Cellular Markers ◽

Α1 Subunit

Nitric oxide (NO) regulates lung development through incompletely understood mechanisms. NO controls pulmonary vascular smooth muscle cell (SMC) differentiation largely through stimulating soluble guanylate cyclase (sGC) to produce cGMP and increase cGMP-mediated signaling. To examine the role of sGC in regulating pulmonary development, we tested whether decreased sGC activity reduces alveolarization in the normal and injured newborn lung. For these studies, mouse pups with gene-targeted sGC-α1 subunit truncation were used because we determined that they have decreased pulmonary sGC enzyme activity. sGC-α1 knockout (KO) mouse pups were observed to have decreased numbers of small airway structures and lung volume compared with wild-type (WT) mice although lung septation and body weights were not different. However, following mild lung injury caused by breathing 70% O2, the sGC-α1 KO mouse pups had pronounced inhibition of alveolarization, as evidenced by an increase in airway mean linear intercept, reduction in terminal airway units, and decrease in lung septation and alveolar openings, as well as reduced somatic growth. Because cGMP regulates SMC phenotype, we also tested whether decreased sGC activity reduces lung myofibroblast differentiation. Cellular markers revealed that vascular SMC differentiation decreased, whereas myofibroblast activation increased in the hyperoxic sGC-α1 KO pup lung. These results indicate that lung development, particularly during hyperoxic injury, is impaired in mouse pups with diminished sGC activity. These studies support the investigation of sGC-targeting agents as therapies directed at improving development in the newborn lung exposed to injury.

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Ontogeny of alpha 1- and beta 1-isoforms of Na(+)-K(+)-ATPase in fetal distal rat lung epithelium

AJP Cell Physiology ◽

10.1152/ajpcell.1993.264.5.c1137 ◽

1993 ◽

Vol 264 (5) ◽

pp. C1137-C1143 ◽

Cited By ~ 36

Author(s):

H. O'Brodovich ◽

O. Staub ◽

B. C. Rossier ◽

K. Geering ◽

J. P. Kraehenbuhl

Keyword(s):

Gestational Age ◽

Lung Development ◽

Mrna Levels ◽

Rat Lung ◽

Slot Blot ◽

Lung Epithelium ◽

Na Transport ◽

Fetal Rats ◽

Distal Lung ◽

Development Levels

Because immature, in contrast to mature, fetal lungs have ineffective Na transport, we wished to determine the ontogeny of Na(+)-K(+)-ATPase expression in fetal distal lung epithelium (FDLE). FDLE and fibroblasts (FLF) from 17- to 22-day gestational age fetal rats (term = 22 days) were grown in primary culture. Northern and slot-blot analyses utilizing isoform-specific cDNA probes determined that alpha 1- (3.7 kb) and beta 1- (2.7, 2.3, and 1.9 kb) transcripts were present in FDLE at levels approximately fivefold higher than in FLF. alpha 2-, alpha 3-, or beta 2-isoforms of Na(+)-K(+)-ATPase were not detected. In 17-day gestational age FDLE, only small amounts of alpha 1-mRNA levels were detectable, and there were approximately 10-fold less beta 1-isoform transcripts. By 20 days gestational age, the level of alpha 1-transcripts roughly doubled, whereas beta 1-levels increased approximately sixfold. Thus, during the transition from the canalicular to saccular stages of lung development, FDLE have a differentially regulated surge in mRNA levels of alpha 1- and beta 1-Na(+)-K(+)-ATPase isoforms and do not switch isoforms during lung development. Levels for both isoform transcripts then fell before birth, reaching values less than those seen for 17-day gestational age FDLE. FDLE vesicle Na(+)-K(+)-ATPase activity did not increase until 22 days gestational age.

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Dexamethasone Effect on Embryonic Chick Respiratory Epithelium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053905 ◽

1982 ◽

Vol 40 ◽

pp. 248-249

Author(s):

M.R. Richter ◽

R.V. Blystone

Keyword(s):

Lung Development ◽

Critical Role ◽

Respiratory Epithelium ◽

Chick Embryos ◽

Embryonic Chick ◽

White Leghorn ◽

Lung Maturation ◽

Synthetic Analogs ◽

Lung Physiology ◽

Avian Lung

Dexamethasone and other synthetic analogs of corticosteroids have been employed clinically as enhancers of lung development. The mechanism(s) by which this steroid induction of later lung maturation operates is not clear. This study reports the effect on lung epithelia of dexamethasone administered at different intervals during development. White Leghorn chick embryos were used so as to remove possible maternal and placental influences on the exogenously applied steroid. Avian lung architecture does vary from mammals; however, respiratory surfactant produced by the lung epithelia serves an equally critical role in avian lung physiology.

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