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.

Vitamin A decreases the incidence and severity of nitrofen-induced congenital diaphragmatic hernia in rats

1999 ◽  
Vol 277 (2) ◽  
pp. L423-L429 ◽  
Author(s):  
Bernard Thébaud ◽  
Dick Tibboel ◽  
Caroline Rambaud ◽  
Jean-Christophe Mercier ◽  
Jacques R. Bourbon ◽  
...  
Keyword(s):  
Vitamin A ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Weight Ratio ◽  
Treated Group ◽  
Control Group ◽  
Lung Growth ◽  
Body Weight Ratio ◽  
Pregnant Rats ◽  
Antenatal Treatment

Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Pulmonary hypoplasia often limits survival. Vitamin A (Vit A) is an important signal for lung growth. We hypothesized that antenatal treatment with Vit A would stimulate lung growth and decrease mortality in experimental CDH induced in rats by ingestion of the herbicide nitrofen (2,4-dichlorophenyl- p-nitrophenyl ether). Nitrofen was administered to pregnant rats on day 12 of gestation (term 22 days). Rats were assigned to five groups: three groups received one dose of oral antenatal Vit A (15,000 IU) before ( day 10), concomitant with ( day 12), or after ( day 14) nitrofen administration; one group received only nitrofen; and a control group received vehicle (olive oil). The incidence of CDH was markedly lower in all groups receiving Vit A ( day 10, 44%; day 12, 20%; and day 14, 40%) compared with the nitrofen-treated group (84%; P < 0.05). The 72-h survival was higher in all 3 Vit A-treated groups ( day 10, 40%; day 12, 58%; and day 14, 70%) compared with the nitrofen-treated group (16%; P< 0.05). Lung-to-body weight ratio and radial saccular count were significantly increased by Vit A. Antenatal treatment with Vit A lowers the incidence and severity of experimental CDH and increases lung growth and maturation.

scholarly journals Changes in the Expression of Vascular Endothelial Growth Factor after Fetal Tracheal Occlusion in an Experimental Model of Congenital Diaphragmatic Hernia

2013 ◽  
Vol 2013 ◽  
pp. 1-6
Author(s):  
E. Sanz-López ◽  
E. Maderuelo ◽  
D. Peláez ◽  
P. Chimenti ◽  
R. Lorente ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Weight Ratio ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Lung Weight ◽  
Tracheal Occlusion ◽  
Endothelial Growth Factor

Introduction. Vascular endothelial growth factor (VEGF), an angiogenic factor secreted by type II pneumocytes, could play a role in congenital diaphragmatic hernia (CDH) pathogenesis. Animal studies suggest that VEGF accelerates lung growth.Aim. To quantify VEGF on fetal lungs in a nitrofen rat model for CDH and to analyze the effect of tracheal occlusion (TO) in VEGF in fetal lung rats after nitrofen and in control rats not exposed to nitrofen.Methods. Pregnant rats received nitrofen on day 9.5 of gestation. Fetuses were divided into 2 groups: those that underwent TO on day 20 and those that did not. On day 21, fetuses were delivered, and the lungs were dissected for subsequent VEGF quantification.Results. CDH was detected in 43% of the fetuses that received nitrofen. Fetuses with CDH showed significantly reduced lung weight/fetal weight ratio and lower VEGF levels than the remainder. A higher VEGF value was observed after TO.Conclusions. VEGF protein was significantly lower in fetuses with CDH. TO induced a significant increase in VEGF compared to the fetuses that did not undergo TO. Although not statistically significant, we observed higher VEGF levels in fetuses with CDH and TO compared to fetuses with CDH and no further intervention.

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.

Effects of tracheal occlusion on the neonatal cardiopulmonary transition in an ovine model of diaphragmatic hernia

2019 ◽  
Vol 104 (6) ◽  
pp. F609-F616 ◽  
Author(s):  
Philip L J DeKoninck ◽  
Kelly J Crossley ◽  
Aidan J Kashyap ◽  
Sasha M Skinner ◽  
Marta Thio ◽  
...  
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Diaphragmatic Hernia ◽  
Weight Ratio ◽  
Lung Compliance ◽  
Ovine Model ◽  
Lung Weight ◽  
Tracheal Occlusion ◽  
Arterial Blood Gas ◽  
Arterial Blood

ObjectiveFetoscopic endoluminal tracheal occlusion (FETO) aims to reverse pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) and mitigate the associated respiratory insufficiency and pulmonary hypertension after birth. We aimed to determine whether FETO improves the cardiopulmonary transition at birth in an ovine model of CDH.MethodsIn 12 ovine fetuses with surgically induced diaphragmatic hernia (DH; 80 dGA), an endotracheal balloon was placed tracheoscopically at ≈110 dGA and removed at ≈131 dGA (DH+FETO), while 10 were left untreated (DH). At ≈138 dGA, all lambs (survival at delivery: 67% [DH+FETO], 70% [DH]) were delivered via caesarean section and ventilated for 2 hours. Physiological and ventilation parameters were continuously recorded, and arterial blood-gas values were measured.ResultsCompared with DH, DH+FETO lambs had increased wet lung-to-body-weight ratio (0.031±0.004 vs 0.016±0.002) and dynamic lung compliance (0.7±0.1 vs 0.4±0.1 mL/cmH2O). Pulmonary vascular resistance was lower in DH+FETO lambs (0.44±0.11 vs 1.06±0.17 mm Hg/[mL/min]). However, after correction for lung weight, pulmonary blood flow was not significantly different between the groups (4.19±0.57 vs 4.05±0.60 mL/min/g). Alveolar–arterial difference in oxygen tension was not significantly different between DH+FETO and DH (402±41mm Hg vs 401±45 mm Hg).ConclusionsFETO accelerated lung growth in fetuses with CDH and improved neonatal respiratory function during the cardiopulmonary transition at birth. However, despite improved lung compliance and reduced pulmonary vascular resistance, there were less pronounced benefits for gas exchange during the first 2 hours of life.

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.

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.

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