scholarly journals Defective mesothelium and limited physical space are drivers of dysregulated lung development in a genetic model of congenital diaphragmatic hernia

Development ◽  
2021 ◽  
Vol 148 (10) ◽  
Author(s):  
Rachel M. Gilbert ◽  
Laurel E. Schappell ◽  
Jason P. Gleghorn
Keyword(s):  
Mouse Model ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Genetic Model ◽  
Ex Vivo ◽  
Physical Space ◽  
Lung Hypoplasia ◽  
Lung Growth ◽  
Knockout Mouse Model ◽  
Chest Cavity

ABSTRACT Congenital diaphragmatic hernia (CDH) is a developmental disorder associated with diaphragm defects and lung hypoplasia. The etiology of CDH is complex and its clinical presentation is variable. We investigated the role of the pulmonary mesothelium in dysregulated lung growth noted in the Wt1 knockout mouse model of CDH. Loss of WT1 leads to intrafetal effusions, altered lung growth, and branching defects prior to normal closure of the diaphragm. We found significant differences in key genes; however, when Wt1 null lungs were cultured ex vivo, growth and branching were indistinguishable from wild-type littermates. Micro-CT imaging of embryos in situ within the uterus revealed a near absence of space in the dorsal chest cavity, but no difference in total chest cavity volume in Wt1 null embryos, indicating a redistribution of pleural space. The altered space and normal ex vivo growth suggest that physical constraints are contributing to the CDH lung phenotype observed in this mouse model. These studies emphasize the importance of examining the mesothelium and chest cavity as a whole, rather than focusing on single organs in isolation to understand early CDH etiology.

scholarly journals Postmortem Characteristics of Lung Hypoplasia at Diaphragmatic Hernia: MRI – Pathomorphological Comparisons

2017 ◽  
pp. 132-142
Author(s):  
U. N. Tumanova ◽  
V. M. Lyapin ◽  
A. A. Burov ◽  
A. I. Shchegolev ◽  
D. N. Degtyarev
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Lung Hypoplasia ◽  
Control Group ◽  
Lung Volumes ◽  
Chest Cavity ◽  
Postmortem Mri ◽  
Group I ◽  
The Mean ◽  
Mri Study

Purpose: the study of postmortem MRI possibilities for the diagnosis of lung hypoplasia in congenital diaphragmatic hernia.Materials and methods. A comparison of the results of postmortem MRI study and data of pathoanatomical autopsy of 23 newborns was performed. In group I, the bodies of 10 deceased newborns with congenital diaphragmatic hernia without operative intervention were examined. In group II – the bodies of 7 newborns who died after surgery for congenital diaphragmatic hernia. Group III (control) included 6 bodies of newborns without diaphragmatic hernia and signs of lung hypoplasia. Before the autopsy, an MRI study was performed on a 3T Magnetom Verio device (Siemens, Germany) in standard T1 and T2 modes. The volumes of the lungs and chest cavity were calculated in the analysis of the tomograms data and their 3D reconstruction. The stage of the lung development and number of radial alveoli were identified at the microscopic study of histological preparations.Results.As a result of the postmortem MRI study, it was established that the observations of group I are characterized by minimal lung volumes. The mean lung volume on the side of the diaphragmatic hernia was 4.1 times less than the contralateral lung (p < 0.01), and the mean values of the volume of both lungs were 4.6 times less than the corresponding values of the control group (p < 0.01) . The average value of the specific volume of the lungs in newborns who died as a result of congenital diaphragmatic hernia (group I) was 8.8%, which is 4.2 times less than the control group (p < 0.01) and was accompanied by histological signs of hypoplasia. The operation in Group II observations led to an increase in lung size. However, the specific volume of the lungs in this group remained by 18.6% less than the control group, and on histological specimens there were signs of lung hypoplasia.Conclusion.The postmortem MRI of dead newborns allows for an objective quantification of lung volumes and verifies the presence of hypoplasia. This helps to clarify the pathogenesis and determine the immediate cause of death. Indices of specific lung volume relative to the chest cavity of less than 20% indicate lung hypoplasia as the immediate cause of death of the newborn.

scholarly journals ROBO2 signaling in lung development regulates SOX2/SOX9 balance, branching morphogenesis and is dysregulated in nitrofen-induced congenital diaphragmatic hernia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ana N. Gonçalves ◽  
Jorge Correia-Pinto ◽  
Cristina Nogueira-Silva
Keyword(s):  
Western Blot ◽  
Congenital Diaphragmatic Hernia ◽  
Progenitor Cells ◽  
Expression Profile ◽  
Diaphragmatic Hernia ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Lung Growth

Abstract Background Characterized by abnormal lung growth or maturation, congenital diaphragmatic hernia (CDH) affects 1:3000 live births. Cellular studies report proximal (SOX2+) and distal (SOX9+) progenitor cells as key modulators of branching morphogenesis and epithelial differentiation, whereas transcriptome studies demonstrate ROBO/SLIT as potential therapeutic targets for diaphragm defect repair in CDH. In this study, we tested the hypothesis that (a) experimental-CDH could changes the expression profile of ROBO1, ROBO2, SOX2 and SOX9; and (b) ROBO1 or ROBO2 receptors are regulators of branching morphogenesis and SOX2/SOX9 balance. Methods The expression profile for receptors and epithelial progenitor markers were assessed by Western blot and immunohistochemistry in a nitrofen-induced CDH rat model. Immunohistochemistry signals by pulmonary structure were also quantified from embryonic-to-saccular stages in normal and hypoplastic lungs. Ex vivo lung explant cultures were harvested at E13.5, cultures during 4 days and treated with increasing doses of recombinant rat ROBO1 or human ROBO2 Fc Chimera proteins for ROBO1 and ROBO2 inhibition, respectively. The lung explants were analyzed morphometrically and ROBO1, ROBO2, SOX2, SOX9, BMP4, and β-Catenin were quantified by Western blot. Results Experimental-CDH induces distinct expression profiles by pulmonary structure and developmental stage for both receptors (ROBO1 and ROBO2) and epithelial progenitor markers (SOX2 and SOX9) that provide evidence of the impairment of proximodistal patterning in experimental-CDH. Ex vivo functional studies showed unchanged branching morphogenesis after ROBO1 inhibition; increased fetal lung growth after ROBO2 inhibition in a mechanism-dependent on SOX2 depletion and overexpression of SOX9, non-phospho β-Catenin, and BMP4. Conclusions These studies provided evidence of receptors and epithelial progenitor cells which are severely affected by CDH-induction from embryonic-to-saccular stages and established the ROBO2 inhibition as promoter of branching morphogenesis through SOX2/SOX9 balance.

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.

Possibility of application of prenatal ultrasound indexes in congenital diaphragmatic hernia in fetus to determine postnatal outcomes

2021 ◽  
Author(s):  
N.V. Mashinets
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Pleural Cavity ◽  
Prenatal Ultrasound ◽  
Lung Hypoplasia ◽  
Prenatal Period ◽  
Compression Index ◽  
Disease Group ◽  
Group I ◽  
Group Ii

Objectives. To assess the effectiveness of the use of prenatal ultrasound indexes in congenital diaphragmatic hernia of the fetus to determine the postnatal prognosis. Materials. The analysis of 95 observations of left-sided congenital diaphragmatic hernia of the fetus was carried out. In the prenatal period, the composition of organs displaced into the pleural cavity was determined, the heart compression index (HCI), O/E LHR according to Jani and DeKoninck, and QLI were calculated. Results. Survival rate of newborns was 57.9%, mortality rate was 42.1%. The newborns were divided into two groups depending on the outcome of the disease. Group I — surviving newborns (n = 55), group II — deceased patients (n = 40). In the analyzed groups, there were no statistical differences in the timing of delivery, birth weight of newborns, the severity of asphyxia after birth and the type of hernia. In group I, the intestinal loops and stomach were significantly more often identified in the pleural cavity in isolation, less often the liver. HCI corresponded to 1.3, Jani O/E LHR 45.7%, DeKoninck O/E LHR 38.7%, QLI 0.7. In group II, concomitant malformations, polyhydramnios and displacement of the liver into the pleural cavity were significantly more frequent. HCI was 1.5, Jani O/E LHR 38.6%, DeKoninck O/E LHR 32.0%, QLI 0.6. Conclusions. In predicting the outcome of the disease for a newborn, the most effective is a comprehensive assessment of the location of the liver, the heart compression index and the index of lung hypoplasia (O/E LHR according to Jani). The diagnostic accuracy of the method is 80%, the sensitivity is 74.4%, and the specificity is 83.3%.

scholarly journals Prenatal Diagnosis and Management of a Rare Central Tendon Defect Type of Congenital Diaphragmatic Hernia with a Massive Pericardial Effusion

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Inas Babic ◽  
Haifa Al-Jobair ◽  
Osama Al Towaijri ◽  
Huda Al-Shammary ◽  
Merna Atiyah ◽  
...  
Keyword(s):  
Pericardial Effusion ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Neonatal Morbidity ◽  
Lung Hypoplasia ◽  
Defect Type ◽  
Tendon Defect ◽  
Prenatal Diagnostic ◽  
Large Pericardial Effusion ◽  
Prenatal Intervention

The central tendon defect type of congenital diaphragmatic hernia (CDH) is extremely rare and usually associated with a significant pericardial effusion. Prenatal diagnostic ultrasound features of this quite rare entity remain often overlooked or misdiagnosed. There is a dearth of literature about the role of prenatal intervention, often through an elective pericardiocentesis, for the prevention of lung hypoplasia and to decrease the overall neonatal morbidity and mortality. To the best of our knowledge, till date, there is only one case that was subjected to a prenatal intervention. Here, we present a second case of a central tendon defect type of CDH with a large pericardial effusion that was subjected to a prenatal transthoracic pericardiocentesis. Although smooth intubation and ventilation were performed immediately after birth, the infant suffered for several months from respiratory instability. Laparoscopic central tendon hernia repair was performed, and neonate was discharged home at seven months of age. Although prenatal pericardiocentesis may facilitate smoother postnatal intubation and ventilation, its broader effect on respiratory function is uncertain and still remains elusive.

scholarly journals Cellular Origin(s) of Congenital Diaphragmatic Hernia

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriëla G. Edel ◽  
Gerben Schaaf ◽  
Rene M. H. Wijnen ◽  
Dick Tibboel ◽  
Gabrielle Kardon ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Birth Defect ◽  
Congenital Disorder ◽  
Diaphragmatic Defect ◽  
Lung Hypoplasia ◽  
Cellular Origin ◽  
Recent Developments ◽  
Mechanical Factors

Congenital diaphragmatic hernia (CDH) is a structural birth defect characterized by a diaphragmatic defect, lung hypoplasia and structural vascular defects. In spite of recent developments, the pathogenesis of CDH is still poorly understood. CDH is a complex congenital disorder with multifactorial etiology consisting of genetic, cellular and mechanical factors. This review explores the cellular origin of CDH pathogenesis in the diaphragm and lungs and describes recent developments in basic and translational CDH research.

Tetralogy of Fallot with congenital diaphragmatic hernia and left lung hypoplasia: assessment of the adequacy of the peripheral pulmonary vascular growth after hernia repair

2011 ◽  
Vol 22 (2) ◽  
pp. 235-238 ◽  
Author(s):  
Hong Ju Shin ◽  
Won Kyoung Jhang ◽  
Tae Jin Yun
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Tetralogy Of Fallot ◽  
Diaphragmatic Hernia ◽  
Left Lung ◽  
Lung Hypoplasia ◽  
Vascular Growth ◽  
Threatening Condition ◽  
Central Pulmonary Artery ◽  
Life Threatening ◽  
Vascular Beds

AbstractCongenital diaphragmatic hernia is a life-threatening condition frequently associated with various congenital cardiac diseases. In congenital diaphragmatic hernia associated with tetralogy of Fallot, central pulmonary artery size of the affected side may not reflect the capacitance of peripheral pulmonary vascular beds. We report a case of congenital diaphragmatic hernia associated with tetralogy of Fallot, which was repaired after assessing the adequacy of the pulmonary vascular beds by intra-operative pulmonary blood flow study.

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

CONGENITAL DIAPHRAGMATIC HERNIA AND HYPOPLASTIC LEFT HEART

PEDIATRICS ◽  
1967 ◽  
Vol 40 (3) ◽  
pp. 329-333
Author(s):  
Frederick N. Firestone ◽  
Robert W. Popper ◽  
Hooshang Taybi ◽  
Richard Leonards
Keyword(s):  
Clinical Trials ◽  
Atrial Septal Defect ◽  
Congenital Diaphragmatic Hernia ◽  
Causal Relationship ◽  
Diaphragmatic Hernia ◽  
Septal Defect ◽  
Left Heart ◽  
Lung Growth ◽  
Hypoplastic Left Heart ◽  
Subsequent Change

An infant with the rare combination of congenital diaphragmatic hernia and hypoplastic left heart has been reported. Although herniated viscera in the chest impair bronchial division and cause hypoplastic lungs, this patient demonstrated lung growth and histologic maturation after successful correction of the diaphragmatic hernia. No subsequent change of the hypoplastic left heart toward normal occurred. There is no apparent causal relationship between these two defects. Creation of an atrial septal defect has been useful in the treatment of hypoplastic left heart. Further clinical trials are encouraged.

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