scholarly journals Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia

2015 ◽  
Vol 308 (7) ◽  
pp. L672-L682 ◽  
Author(s):  
Martine Makanga ◽  
Hidekazu Maruyama ◽  
Celine Dewachter ◽  
Agnès Mendes Da Costa ◽  
Emeline Hupkens ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Body Weight ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Weight Ratio ◽  
The Body ◽  
Lung Hypoplasia ◽  
External Diameter ◽  
Pathological Features ◽  
Pulmonary Vessel

Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Simvastatin has been shown to prevent the development of pulmonary hypertension (PH) in experimental models of PH. We, therefore, hypothesized that antenatal simvastatin would attenuate PPHN in nitrofen-induced CDH in rats. The efficacy of antenatal simvastatin was compared with antenatal sildenafil, which has already been shown to improve pathological features of PPHN in nitrofen-induced CDH. On embryonic day (E) 9.5, nitrofen or vehicle was administered to pregnant Sprague-Dawley rats. On E11, nitrofen-treated rats were randomly assigned to antenatal simvastatin (20 mg·kg−1·day−1 orally), antenatal sildenafil (100 mg·kg−1·day−1 orally), or placebo administration from E11 to E21. On E21, fetuses were delivered by cesarean section, killed, and checked for left-sided CDH. Lung tissue was then harvested for further pathobiological evaluation. In nitrofen-induced CDH, simvastatin failed to reduce the incidence of nitrofen-induced CDH in the offspring and to increase the body weight, but improved the lung-to-body weight ratio and lung parenchyma structure. Antenatal simvastatin restored the pulmonary vessel density and external diameter, and reduced the pulmonary arteriolar remodeling compared with nitrofen-induced CDH. This was associated with decreased lung expression of endothelin precursor, endothelin type A and B receptors, endothelial and inducible nitric oxide synthase, together with restored lung activation of apoptotic processes mainly in the epithelium. Antenatal simvastatin presented similar effects as antenatal therapy with sildenafil on nitrofen-induced CDH. Antenatal simvastatin improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.

Lung Pathology in Patients with Congenital Diaphragmatic Hernia Treated with Fetal Surgical Intervention, Including Tracheal Occlusion

2003 ◽  
Vol 6 (6) ◽  
pp. 536-546 ◽  
Author(s):  
Amy E. Heerema ◽  
Joseph T. Rabban ◽  
Roman M. Sydorak ◽  
Micheal R. Harrison ◽  
Kirk D. Jones
Keyword(s):  
Body Weight ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Pulmonary Hypoplasia ◽  
Weight Ratio ◽  
Lung Pathology ◽  
Body Weight Ratio ◽  
Fetal Intervention ◽  
Tracheal Occlusion ◽  
Significant Difference

Fetal intervention for congenital diaphragmatic hernia was developed to lessen the high morbidity and mortality of pulmonary hypoplasia. Lung pathology and morphometry in patients treated with fetal intervention have not been described. We report clinical and autopsy findings, as well as basic lung morphometry in 16 cases of congenital diaphragmatic hernia with fetal intervention (12 cases tracheal occlusion; 4 cases hernia repair), and 19 cases of congenital diaphragmatic hernia without fetal intervention. All patients who underwent fetal intervention were born premature. Lung enlargement with increased lung-to-body weight ratio was observed with fetal tracheal occlusion, accompanied by lower than normal radial alveolar counts and increased alveolar size. Patients treated with tracheal occlusion also had early alveolar development (at 29.8, 30.6, and 30.9 wk postconceptual age) as well as mucous fluid pooling in airways and alveoli. All cases showed severe alveolar septal widening, more extensive in patients without fetal intervention. When grouped by postconceptual age, no statistically significant difference was found between patients with and without fetal intervention with respect to lung-to-body weight ratio, radial alveolar count, mean alveolar length, and relative arteriolar media thickness. Lung enlargement has been observed with fetal tracheal occlusion sonographically; our studies suggest that this is due in part to emphysema and mucous fluid pooling. The lung remains abnormal with low radial alveolar counts and increased alveolar size. Tracheal occlusion did not prevent development of lung pathology associated with pulmonary hypoplasia.

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

2015 ◽  
Vol 39 (2) ◽  
pp. 125-133 ◽  
Author(s):  
Mary Patrice Eastwood ◽  
Anouck Kampmeijer ◽  
Julio Jimenez ◽  
Silvia Zia ◽  
Rieta Vanbree ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rabbit Model ◽  
Weight Ratio ◽  
Surfactant Protein ◽  
Pulmonary Vessel ◽  
Fetal Survival ◽  
Vessel Morphology ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Objective: Glucagon-like peptide-1 (GLP-1) increases surfactant protein expression in type 2 pneumocytes. Herein, we determine if transplacental GLP-1 treatment accelerates lung growth in the fetal rabbit model of congenital diaphragmatic hernia (DH). Methods: Time-mated does had an induction of DH on day 23 followed by daily GLP-1 or placebo injection until term. At that time, the does were weighed, fetal blood was obtained for GLP-1 assay, and the lungs were dissected. Fetal outcome measures were lung-to-body-weight ratio (LBWR), morphometry, and Ki67 and surfactant protein B (SPB) expression. Results: Maternal weight loss in the GLP-1 group was 7.1%. Fetal survival was lower in GLP-1 fetuses compared to placebo controls (27/85, 32% vs. 35/57, 61%; p < 0.05). Fetal GLP-1 levels were increased 3.6-fold. The LBWR of GLP-1 DH fetuses fell within the range of DH placebo fetuses (1.166 ± 0.207% vs. 1.312 ± 0.418%), being significantly lower than that of placebo-exposed unoperated fetuses (2.280 ± 0.522%; p < 0.001). GLP-1 did not improve airway morphometry. GLP-1 DH lungs had a reduced adventitial and medial thickness within the range of controls, and lesser muscularization of vessels measuring 30-60 µm. There were no differences in Ki67 and SPB expression. Conclusion: GLP-1 at this dosage improves peripheric pulmonary vessel morphology in intra-acinar vessels with no effect on airway morphometry but with significant maternal and fetal side effects. Thus, it is an unlikely medical strategy.

scholarly journals Heart hypoplasia in an animal model of congenital diaphragmatic hernia

2001 ◽  
Vol 56 (6) ◽  
pp. 173-178 ◽  
Author(s):  
Uenis Tannuri
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Experimental Model ◽  
Diaphragmatic Hernia ◽  
Interventricular Septum ◽  
Left Lung ◽  
Therapeutic Strategies ◽  
Left Lobe ◽  
The Body ◽  
Lung Hypoplasia ◽  
The Right

PURPOSE: In previous papers, we described a new experimental model of congenital diaphragmatic hernia in rabbits, and we also reported noninvasive therapeutic strategies for prevention of the functional and structural immaturity of the lungs associated with this defect. In addition to lung hypoplasia, pulmonary hypertension, biochemical, and structural immaturity of the lungs, the hemodynamics of infants and animals with congenital diaphragmatic hernia are markedly altered. Hence, cardiac hypoplasia has been implicated as a possible cause of death in patients with congenital diaphragmatic hernia, and it is hypothesized to be a probable consequence of fetal mediastinal compression by the herniated viscera. Cardiac hypoplasia has also been reported in lamb and rat models of congenital diaphragmatic hernia. The purpose of the present experiment was to verify the occurrence of heart hypoplasia in our new model of surgically produced congenital diaphragmatic hernia in fetal rabbits. METHODS: Twelve pregnant New Zealand rabbits underwent surgery on gestational day 24 or 25 (normal full gestational time - 31 to 32 days) to create left-sided diaphragmatic hernias in 1 or 2 fetuses per each doe. On gestational day 30, all does again underwent surgery, and the delivered fetuses were weighed and divided into 2 groups: control (non-surgically treated fetuses) (n = 12) and congenital diaphragmatic hernia (n = 9). The hearts were collected, weighed, and submitted for histologic and histomorphometric studies. RESULTS: During necropsy, it was noted that in all congenital diaphragmatic hernia fetuses, the left lobe of the liver herniated throughout the surgically created defect and occupied the left side of the thorax, with the deviation of the heart to the right side, compressing the left lung; consequently, this lung was smaller than the right one. The body weights of the animals were not altered by congenital diaphragmatic hernia, but heart weights were decreased in comparison to control fetuses. The histomorphometric analysis demonstrated that congenital diaphragmatic hernia promoted a significant decrease in the ventricular wall thickness and an increase in the interventricular septum thickness. CONCLUSION: Heart hypoplasia occurs in a rabbit experimental model of congenital diaphragmatic hernia. This model may be utilized for investigations in therapeutic strategies that aim towards the prevention or the treatment of heart hypoplasia caused by congenital diaphragmatic hernia.

scholarly journals Genetics of diaphragmatic hernia

2021 ◽  
Author(s):  
Yannick Schreiner ◽  
Thomas Schaible ◽  
Neysan Rafat
Keyword(s):  
Pulmonary Hypertension ◽  
Clinical Outcome ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Congenital Malformations ◽  
Lung Hypoplasia ◽  
Complex Phenotype ◽  
Life Threatening ◽  
Major Congenital Malformations ◽  
Very High

AbstractCongenital diaphragmatic hernia (CDH) is a life-threatening malformation characterised by failure of diaphragmatic development with lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). The incidence is 1:2000 corresponding to 8% of all major congenital malformations. Morbidity and mortality in affected newborns are very high and at present, there is no precise prenatal or early postnatal prognostication parameter to predict clinical outcome in CDH patients. Most cases occur sporadically, however, genetic causes have long been discussed to explain a proportion of cases. These range from aneuploidy to complex chromosomal aberrations and specific mutations often causing a complex phenotype exhibiting multiple malformations along with CDH. This review summarises the genetic variations which have been observed in syndromic and isolated cases of congenital diaphragmatic hernia.

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 Lung Transplantation for Late-Onset Pulmonary Hypertension in a Patient with Congenital Diaphragmatic Hernia

2018 ◽  
Vol 06 (01) ◽  
pp. e100-e103
Author(s):  
Chiara Iacusso ◽  
Francesco Morini ◽  
Irma Capolupo ◽  
Andrea Dotta ◽  
Stefania Sgrò ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Respiratory Failure ◽  
Lung Transplantation ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Late Onset ◽  
Severe Malnutrition ◽  
Lung Hypoplasia ◽  
Tract Infections ◽  
End Stage

AbstractLung hypoplasia and pulmonary hypertension (PH) in association with congenital diaphragmatic hernia (CDH) may cause fatal respiratory failure. Lung transplantation (Ltx) may represent an option for CDH-related end-stage pulmonary failure. The aim of this study is to report a patient with CDH who underwent Ltx or combined heart-lung transplantation (H-Ltx). Our patient was born at 33 weeks of gestation, with a prenatally diagnosed isolated left CDH. Twenty-four hours after birth, she underwent surgical repair of a type D defect (according to the CDH Study Group staging system). Postoperative course was unexpectedly uneventful, and she was discharged home at 58 days of life. Echocardiography before discharge was unremarkable. Periodic follow-up revealed gastroesophageal reflux (GER) and initial scoliosis. At the age of 10, she was readmitted for severe PH. Lung function progressively deteriorated, and at the age of 14, she underwent H-Ltx due to end-stage respiratory failure. After discharge, she developed recurrent respiratory tract infections, severe malnutrition, and drug-induced diabetes. Scoliosis and GER progressed, requiring posterior vertebral arthrodesis and antireflux surgery, respectively. Bronchiolitis obliterans further impaired her respiratory function, and though she had a second Ltx, she died at the age of 18, 4 and 1.5 years after the first and the second Ltx, respectively. Late-onset PH is an ominous complication of CDH. From our patient and the six further cases collected from the literature, Ltx may be considered as a last-resource treatment in CDH patients with irreversible and fatal respiratory failure, although its prognosis seems unfair.

Neonatal cardiopulmonary transition in an ovine model of congenital diaphragmatic hernia

2019 ◽  
Vol 104 (6) ◽  
pp. F617-F623 ◽  
Author(s):  
Aidan J Kashyap ◽  
Kelly J Crossley ◽  
Philip L J DeKoninck ◽  
Karyn A Rodgers ◽  
Marta Thio ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Cerebral Oxygenation ◽  
Weight Ratio ◽  
Respiratory Acidosis ◽  
Tissue Oxygen Saturation ◽  
Lung Hypoplasia ◽  
Ovine Model ◽  
Lung Weight ◽  
Arterial Blood

ObjectiveInfants with a congenital diaphragmatic hernia (CDH) are at high risk of developing pulmonary hypertension after birth, but little is known of their physiological transition at birth. We aimed to characterise the changes in cardiopulmonary physiology during the neonatal transition in an ovine model of CDH.MethodsA diaphragmatic hernia (DH) was surgically created at 80 days of gestational age (dGA) in 10 fetuses, whereas controls underwent sham surgery (n=6). At 138 dGA, lambs were delivered via caesarean section and ventilated for 2 hours. Physiological and ventilation parameters were continuously recorded, and arterial blood gas values were measured.ResultsDH lambs had lower wet lung-to-body-weight ratio (0.016±0.002vs0.033±0.004), reduced dynamic lung compliance (0.4±0.1mL/cmH2O vs1.2±0.1 mL/cmH2O) and reduced arterial pH (7.11±0.05vs7.26±0.05), compared with controls. While measured pulmonary blood flow (PBF) was lower in DH lambs, after correction for lung weight, PBF was not different between groups (4.05±0.60mL/min/gvs4.29±0.57 mL/min/g). Cerebral tissue oxygen saturation was lower in DH compared with control lambs (55.7±3.5vs67.7%±3.9%).ConclusionsImmediately after birth, DH lambs have small, non-compliant lungs, respiratory acidosis and poor cerebral oxygenation that reflects the clinical phenotype of human CDH. PBF (indexed to lung weight) was similar in DH and control lambs, suggesting that the reduction in PBF associated with CDH is proportional to the degree of lung hypoplasia during the neonatal cardiopulmonary transition.

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