scholarly journals Lung hypoplasia in the nitrofen model of congenital diaphragmatic hernia occurs early in development

2000 ◽  
Vol 279 (6) ◽  
pp. L1159-L1171 ◽  
Author(s):  
Theresa W. Guilbert ◽  
Sarah A. Gebb ◽  
John M. Shannon
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Pulmonary Hypoplasia ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Lung Hypoplasia ◽  
Pregnant Rats ◽  
Terminal End Buds ◽  
Surfactant Protein B ◽  
Endothelial Growth Factor

The teratogen nitrofen produces a congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia in rodent fetuses that closely parallel observations made in humans. We hypothesized that these changes may be due to primary pulmonary hypoplasia and not herniation of the abdominal contents. Timed-pregnant rats were given nitrofen on day 9, and fetuses were harvested on days 13 through 21. Initial evagination of lung buds on gestational day 11 was not delayed in nitrofen-treated fetuses. On gestational day 13, however, there was a significant decrease in the number of terminal end buds in the lungs of nitrofen-exposed fetuses vs. controls. Thymidine-labeled lung epithelial and mesenchymal cells were significantly decreased in nitrofen-treated lungs. Lungs from nitrofen-treated fetuses exhibited wide septae with disorganized, compacted tissue, particularly around the air spaces. Expression of surfactant protein B and C mRNAs was significantly decreased in the nitrofen litters. In situ hybridization of fetal lung tissue at all gestational ages showed no difference in the expression of vascular endothelial growth factor, Flk-1, or Flt-1 mRNAs. Because closure of the diaphragm is completed on gestational day 16 in the rat, our results suggest that lung hypoplasia in this model of CDH is due at least in part to a primary effect of nitrofen on the developing lung.

scholarly journals Amniotic fluid stem cell extracellular vesicles promote fetal lung branching and cell differentiation in experimental congenital diaphragmatic hernia

2022 ◽  
Author(s):  
Kasra Khalaj ◽  
Rebeca Lopes Figueira ◽  
Lina Antounians ◽  
Sree Gandhi ◽  
Matthew Wales ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Congenital Diaphragmatic Hernia ◽  
Extracellular Vesicles ◽  
Diaphragmatic Hernia ◽  
Lung Development ◽  
Pulmonary Hypoplasia ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Neuroendocrine Cells ◽  
Beta Catenin

Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by impaired branching morphogenesis and differentiation. We have previously demonstrated that administration of extracellular vesicles derived from rat amniotic fluid stem cells (AFSC-EVs) rescues development of hypoplastic lungs at the pseudoglandular and alveolar stages in rodent models of CDH. Herein, we tested whether AFSC-EVs exert their regenerative effects at the canalicular and saccular stages, as these are translationally relevant for clinical intervention. To induce fetal pulmonary hypoplasia, we gavaged rat dams with nitrofen at embryonic day 9.5 and demonstrated that nitrofen-exposed lungs had impaired branching morphogenesis, dysregulated signaling pathways relevant to lung development (FGF10/FGFR2, ROBO/SLIT, Ephrin, Neuropilin 1, beta-catenin) and impaired epithelial and mesenchymal cell marker expression at both stages. AFSC-EVs administered to nitrofen-exposed lung explants rescued airspace density and increased the expression levels of key factors responsible for branching morphogenesis. Moreover, AFSC-EVs rescued the expression of alveolar type 1 and 2 cell markers at both canalicular and saccular stages, and restored markers of club, ciliated epithelial, and pulmonary neuroendocrine cells at the saccular stage. AFSC-EV treated lungs also had restored markers of lipofibroblasts and PDGFRA+ cells to control levels at both stages. EV tracking showed uptake of AFSC-EV RNA cargo throughout the fetal lung and an mRNA-miRNA network analysis identified that several miRNAs responsible for regulating lung development processes were contained in the AFSC-EV cargo. These findings suggest that AFSC-EV based therapies hold potential for restoring fetal lung growth and maturation in babies with pulmonary hypoplasia secondary to CDH.

Lipocalin 2 as a new biomarker for fetal lung hypoplasia in congenital diaphragmatic hernia

2016 ◽  
Vol 462 ◽  
pp. 71-76 ◽  
Author(s):  
Hiroyuki Tsuda ◽  
Tomomi Kotani ◽  
Tomoko Nakano ◽  
Kenji Imai ◽  
Shima Hirako ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Fetal Lung ◽  
Lung Hypoplasia ◽  
Lipocalin 2

scholarly journals Impaired surfactant protein B synthesis in infants with congenital diaphragmatic hernia

2012 ◽  
Vol 41 (3) ◽  
pp. 677-682 ◽  
Author(s):  
Paola E. Cogo ◽  
Manuela Simonato ◽  
Olivier Danhaive ◽  
Giovanna Verlato ◽  
Giovanna Cobellis ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Surfactant Protein ◽  
Surfactant Protein B ◽  
Protein B

scholarly journals Motion corrected fetal body MRI provides reliable 3D lung volumes in normal and abnormal fetuses

2021 ◽  
Author(s):  
Joseph Davidson ◽  
Alena Uus ◽  
Alexia Egloff Collado ◽  
Milou Van Poppel ◽  
Jacqueline Matthew ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Lung Volume ◽  
Fetal Mri ◽  
Fetal Lung ◽  
Lung Hypoplasia ◽  
Healthy Controls ◽  
Lung Volumes ◽  
Total Lung Volume ◽  
Volume Registration

Abstract Objective:Evaluate deformable slice-to-volume registration (DSVR) to calculate 3D-segmented total lung volume (TLV) in fetuses with congenital diaphragmatic hernia, congenital lung lesions and healthy controls, with comparison to 2D-manual segmentation. Design:Pilot study Setting:Regional fetal medicine referral centre Sample:Fetal MRIs performed for clinical indications (abnormal cases) or as research participants (healthy controls) Methods:Sixteen MRI datasets of fetuses (22-32 weeks GA). Diagnosis: CDH(n=5), CPAM(n=2), CDH with BPS(n=1) and healthy control(n=8). DSVR was used for reconstruction of 3D isotropic (0.85 mm) volumes of fetal body followed by semi-automated lung segmentation. The resulting 3D TLV were compared to the traditional 2D-based volumetry, and a normogram of DSVR-derived fetal lung volumes from 100 cases was produced. Main Outcome Measures:Concordance with 2D-volumetry assessed with Bland-Altman analysis, results of segmentations presented visually. Observed/Expected values were calculated for abnormal cases based upon the normogram. Results:DSVR-derived TLV values have high correlation with the 2D-based measurements but with a consistently lower volume; bias -1.44cm3 [95% limits: -2.6 to -0.3] with improved resolution able to exclude hilar structures even in severe motion corruption or in cases of lung hypoplasia. Conclusions:Application of DSVR for fetal MRI provides a solution for analysis of motion corrupted scans and does not suffer from the interpolation error inherent in 2D-segmentation as per current clinical practice. It increases information content of acquired data in terms of visualising organs in 3D space and quantification of volumes, which we believe will have important value for counselling and surgical planning. Keywords:Fetal MRI; congenital diaphragmatic hernia; CPAM; lung volume

scholarly journals STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

2017 ◽  
Vol 45 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Paulina Piairo ◽  
Rute S. Moura ◽  
Maria João Baptista ◽  
Jorge Correia-Pinto ◽  
Cristina Nogueira-Silva
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Lung Development ◽  
Pulmonary Hypoplasia ◽  
Fetal Lung ◽  
Developmental Expression ◽  
Lung Growth ◽  
Growth Modulation ◽  
Late Expression

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. Methods: We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. Results: Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. Conclusion: These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH.

Fetal tracheal occlusion in the rat model of nitrofen-induced congenital diaphragmatic hernia

1999 ◽  
Vol 87 (2) ◽  
pp. 769-775 ◽  
Author(s):  
Yoshihiro Kitano ◽  
Paul Davies ◽  
Daniel von Allmen ◽  
N. Scott Adzick ◽  
Alan W. Flake
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Weight Ratio ◽  
Lung Parenchyma ◽  
Lung Hypoplasia ◽  
Lung Growth ◽  
Lung Weight ◽  
Pregnant Rats ◽  
Tracheal Occlusion

Prenatal tracheal occlusion (TO) consistently accelerates lung growth in the sheep model of congenital diaphragmatic hernia (CDH). However, significant variability in lung growth has been observed in early clinical trials of TO. We hypothesized that lung hypoplasia created at relatively late stages of lung development may not be equivalent to human CDH-induced lung hypoplasia, which begins early in gestation. To test this hypothesis, we performed TO in the rat model of nitrofen-induced CDH. Left-sided CDH was induced by administering 100 mg of nitrofen to timed pregnant rats on day 9 of gestation. On day 19 of gestation, four to five fetuses per dam underwent surgical ligation of the trachea. At death ( day 21.5), lungs from non-CDH (non-CDH group), left-CDH (CDH group), and trachea-occluded left-CDH fetuses (CDH-TO group) were harvested and compared by weight, DNA and protein content, and stereological morphometry. Wet and dry lung weight-to-body weight ratio, total lung DNA and protein contents, the volume of lung parenchyma, and the total saccular surface area of the CDH-TO group were significantly increased relative to the CDH group and were either greater than or comparable to the non-CDH controls. We conclude that TO accelerates lung growth and increases lung parenchyma in an early-onset model of CDH-induced lung hypoplasia.

scholarly journals 495 Impaired Surfactant Protein B Synthesis in Infants with Congenital Diaphragmatic Hernia

2010 ◽  
Vol 68 ◽  
pp. 253-254
Author(s):  
P E Cogo ◽  
M Simonato ◽  
O Danhaive ◽  
A Baritussio ◽  
L Vedovelli ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Surfactant Protein ◽  
Surfactant Protein B ◽  
Protein B

Expression of Angiogenesis-Related Factors in Lungs of Patients with Congenital Diaphragmatic Hernia and Pulmonary Hypoplasia of Other Causes

2004 ◽  
Vol 7 (5) ◽  
pp. 468-477 ◽  
Author(s):  
Jessica D. de Rooij ◽  
Münnever Hösgör ◽  
Ynske Ijzendoorn ◽  
Robbert Rottier ◽  
Frederick A. Groenman ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Molecular Mechanisms ◽  
Pulmonary Hypoplasia ◽  
Fetal Liver ◽  
Expression Patterns ◽  
Pulmonary Arteries ◽  
Lung Hypoplasia ◽  
Related Factors ◽  
Total Size

Congenital diaphragmatic hernia (CDH) is a congenital disorder, complicated by pulmonary hypoplasia (PH) and pulmonary hypertension. Hypoplastic lungs have fewer and smaller airspaces than normal, with thicker interalveolar septa; the adventitia and media of pulmonary arteries are thickened, and the total size of the pulmonary vascular bed is decreased compared to normal. Although histological abnormalities in PH have been described, less is known about the underlying molecular mechanisms. Therefore, we have investigated a series of proteins, known to be involved in angiogenesis, including von Hippel-Lindau protein (pVHL), hypoxia-inducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), fetal liver kinase 1 (Flk-1), and endothelial and inducible nitric oxide synthase (eNOS, iNOS) by immunohistochemistry on paraffin-embedded lung tissue of CDH patients (n = 13), patients with lung hypoplasia due to other causes (n = 20), and normal controls (n = 33). pVHL was expressed more frequently in the arterial smooth muscle cells of CDH lungs compared with both other groups. Furthermore, HIF-1a was expressed less frequently in the endothelium of arteries, veins, and capillaries of CDH lungs as compared with both other groups. No differences were observed in the expression patterns of VEGF, Flk-1, eNOS, and iNOS between the different groups. Our data suggest a role for pVHL and HIF-1a in normal and abnormal pulmonary angiogenesis. The differential expression of these proteins may provide a molecular basis for the histological differences observed in the lung vessels of patients with CDH.

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