Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia

doi:10.1016/j.jpedsurg.2017.12.002

Journal of Pediatric Surgery

Volume 53, Issue 9, September 2018, Pages 1681-1687

https://doi.org/10.1016/j.jpedsurg.2017.12.002 Get rights and content

Abstract

Background

Lung and pulmonary vascular maldevelopment in congenital diaphragmatic hernia (CDH) results in significant morbidity and mortality. Retinoic acid (RA) and imatinib have been shown to improve pulmonary morphology following prenatal administration in the rat nitrofen-induced CDH model. It remains unclear if these changes translate into improved function. We evaluated the effect of prenatal RA and imatinib on postnatal lung function, structure, and pulmonary artery (PA) blood flow in the rat CDH model.

Methods

Olive oil or nitrofen was administered alone or in combination with RA or imatinib to pregnant rats. Pups were assessed for PA blood flow by ultrasound and pulmonary function/morphology following delivery, intubation, and short-term ventilation.

Results

Neither RA nor imatinib had a negative effect on lung and body growth. RA accelerated lung maturation indicated by increased alveoli number and thinner interalveolar septa and was associated with decreased PA resistance and improved oxygenation. With the exception of a decreased PA pulsatility index, no significant changes in morphology and pulmonary function were noted following imatinib.

Conclusion

Prenatal treatment with RA but not imatinib was associated with improved pulmonary morphology and function, and decreased pulmonary vascular resistance. This study highlights the potential of prenatal pharmacologic therapies, such as RA, for management of CDH.

Section snippets

Animal model

Time-dated pregnant Sprague–Dawley rats were gavage fed 100 mg of nitrofen (Sigma-Aldrich, St. Louis, MO) dissolved in 1 mL olive oil at embryonic (E) day 9.5 to create a prenatal CDH. Dams were randomized into 2 treatment groups; (1) Vitamin A: All-trans Retinoic Acid (ATRA) (Sigma-Aldrich) dissolved in olive oil (10 mg/mL) was administered intraperitoneally from E18.5 to E20.5 at a dose of 5 mg/kg as previously described [11], [12]; (2) imatinib (Gleevec®, Novartis) dissolved in normal saline was

Lung weight (Lw) to body weight (Bw) ratio (Lw/Bw)

The effect of prenatal RA or imatinib administration on fetal lung and overall body growth was evaluated. The Lw/Bw ratio was significantly decreased in newborn CDH pups compared to both controls and nitrofen exposed fetuses without CDH as previously shown [23]. Prenatal administration of RA or imatinib did not significantly affect the Lw/Bw ratio in CDH pups compared to nontreated CDH pups (Fig. 1a).

Ventilation

Tidal volumes (Vt) were measured following ventilation for 30 min after birth. As has been shown

Discussion

Significant advances in neonatal and surgical care have improved outcomes for many patients with CDH. Despite these advances, survival rates of CDH infants remain low at 68%–92% with significant morbidity and mortality attributed to pulmonary hypertension and hypoplasia [34], [35], [36]. The ability to prenatally diagnose a CDH as well as predict its severity [37], [38], [39], [40] offers the potential to introduce therapies for fetuses with the most severe defects prior to birth. The goal of

Acknowledgments

This work was supported by generous family gifts to The Children's Hospital of Philadelphia. The authors would like to thank Ms. Antoneta Radu and Mr. Aaron Weilerstein for their help with histology and animal care respectively.

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Antenatal Administration of Extracellular Vesicles Derived From Amniotic Fluid Stem Cells Improves Lung Function in Neonatal Rats With Congenital Diaphragmatic Hernia
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The severity of pulmonary hypoplasia is a main determinant of outcome for babies with congenital diaphragmatic hernia (CDH). Antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) has been shown to rescue morphological features of lung development in the rat nitrofen model of CDH. Herein, we evaluated whether AFSC-EV administration to fetal rats with CDH is associated with neonatal improvement in lung function.
AFSC-EVs were isolated by ultracentrifugation and characterized by size, morphology, and canonical marker expression. At embryonic (E) day 9.5, dams were gavaged with olive oil (control) or nitrofen to induce CDH. At E18.5, fetuses received an intra-amniotic injection of either saline or AFSC-EVs. At E21.5, rats were delivered and subjected to a tracheostomy for mechanical ventilation (flexiVent system). Groups were compared for lung compliance, resistance, Newtonian resistance, tissue damping and elastance. Lungs were evaluated for branching morphogenesis and collagen quantification.
Compared to healthy control, saline-treated pups with CDH had fewer airspaces, more collagen deposition, and functionally exhibited reduced compliance and increased airway resistance, elastance, and tissue damping. Conversely, AFSC-EV administration resulted in improvement of lung mechanics (compliance, resistance, tissue damping, elastance) as well as lung branching morphogenesis and collagen deposition.
Our studies show that the rat nitrofen model reproduces lung function impairment similar to that of human babies with CDH. Antenatal administration of AFSC-EVs improves lung morphology and function in neonatal rats with CDH.
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Characterization of the congenital diaphragmatic hernia model in C57BL/6J fetal mice: a step toward lineage tracing experiments
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^☆: Author Roles: CMB designed the study, performed the experiments, analyzed the data, and wrote the paper; MD designed the study, analyzed the data, provided critical analytical advice, and wrote the paper; JSR performed the experiments and analyzed the data; HJ performed the experiments and analyzed the data, AWF provided critical analytical advice; WHP designed the study, analyzed the data, provided critical analytical advice, and wrote the paper.

^☆☆: Conflicts of Interest: The authors declare no conflicts of interest.

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Original ArticleLung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia☆,☆☆

Abstract

Background

Methods

Results

Conclusion

Section snippets

Animal model

Lung weight (Lw) to body weight (Bw) ratio (Lw/Bw)

Ventilation

Discussion

Acknowledgments

Semin Perinatol

Semin Perinatol

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

Cytokine Growth Factor Rev

Eur J Obstet Gynecol Reprod Biol

J Am Soc Echocardiogr

Eur J Obstet Gynecol Reprod Biol

Am J Cardiol

Semin Pediatr Surg

J Pediatr Surg

Best Pract Res Clin Obstet Gynaecol

J Pediatr Surg

Semin Perinatol

Semin Pediatr Surg

Surgery

J Pediatr Surg

Am J Obstet Gynecol

J Pediatr Surg

J Pediatr Surg

Post-mortem findings in fetal and neonatal congenital diaphragmatic hernia

Eur J Pediatr Surg

Fetal lung growth in congenital diaphragmatic hernia

Fetal Diagn Ther

Postmortem findings and clinicopathological correlation in congenital diaphragmatic hernia

Pediatr Dev Pathol

Endothelin receptor expression in human lungs of newborns with congenital diaphragmatic hernia

J Pathol

Expression of angiogenesis-related factors in lungs of patients with congenital diaphragmatic hernia and pulmonary hypoplasia of other causes

Pediatr Dev Pathol

Congenital diaphragmatic hernia

Eur Respir J

Original Article
Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia☆,☆☆