Platelet-derived growth factor inhibition—a new treatment of pulmonary hypertension in congenital diaphragmatic hernia?

doi:10.1016/j.jpedsurg.2008.07.022

Journal of Pediatric Surgery

Volume 43, Issue 10, October 2008, Pages 1928-1931

https://doi.org/10.1016/j.jpedsurg.2008.07.022 Get rights and content

Abstract

Increased pulmonary vascular resistance causing pulmonary artery hypertension is a major problem in the treatment of congenital diaphragmatic hernia with a strong association to mortality. We here report a patient with intractable pulmonary hypertension at 4 weeks of age unresponsive to conventional treatment. After administration of the platelet-derived growth factor (PDGF) receptor antagonist imatinib, pulmonary artery pressure gradually decreased to acceptable levels and the patient's clinical condition gradually improved.

Section snippets

Case report

The patient was born at a small district hospital in the north of Sweden at gestational age 38 + 4 weeks by abdominal delivery weighing 2660 g. Apgar scores were 6, 6, and 7 at 1, 5, and 10 minutes, respectively. There was no prenatal diagnosis. Lack of breath sounds on the left side and chest x-ray quickly confirmed a suspected diagnosis of CDH, and the patient was treated initially with 100% oxygen and continuous positive airway pressure (CPAP). Initial saturation was between 70% and 80%, and

Discussion

Platelet-derived growth factor is a potent mitogen and is one of several growth factors involved in proliferation of smooth muscle cells. In lung biopsies from patients with severe PAH, the expression of PDGF was increased [8]. Platelet-derived growth factor acts through stimulation of the PDGF receptors (PDGFRs), which belong to a family of receptor tyrosine kinases. It promotes the proliferation and migration of pulmonary artery smooth muscle cells indicating that PDGF is involved in vascular

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Cited by (19)

Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia
2018, Journal of Pediatric Surgery
Citation Excerpt :
In addition to the morphological improvement of the hypoplastic lungs after antenatal administration of RA, we also demonstrated a beneficial effect on lung function, with improved oxygenation and reduced pressure in the PA. Imatinib, a PDGF-R antagonist, has been successfully used in the treatment of a CDH patient with intractable pulmonary hypertension [53]. It has been demonstrated to reduce the medial wall thickness and restore the luminal area in pulmonary arteries in the nitrofen-induced CDH rat model [22].
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.
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.
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.
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.
Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia
2014, Seminars in Fetal and Neonatal Medicine
Citation Excerpt :
In the nitrofen-induced CDH rat model, imatinib treatment lead to a decreased vascular media wall thickness which may be mediated by decreased PDGF expression and smooth muscle cell proliferation [42]. Though imatinib has not been used prenatally, it has been used successfully for treatment of pulmonary hypertension in a neonate with CDH [43]. In conclusion, over the past 20 years, many treatments have been attempted to address pulmonary hypoplasia, immaturity, and hypertension in utero for patients with CDH.
This review focuses on the emerging field of non-surgical in-utero therapies in the management of fetal pulmonary hypoplasia and pulmonary hypertension associated with congenital diaphragmatic hernia (CDH). These experimental approaches include pharmacologic as well as stem-cell-based strategies. Current barriers of non-surgical therapies toward clinical translation are emphasized. As the severity of CDH will likely influence the efficacy of any in-utero therapy, the current status of prenatal imaging and the role of novel biomarkers, especially those related to fetal inflammation, are also reviewed.
Controversies in the management of severe congenital diaphragmatic hernia
2014, Seminars in Fetal and Neonatal Medicine
Citation Excerpt :
Although there is need for further studies, the result of this elegant experimental study opens new therapeutic opportunities for medical prenatal strategies to improve the outcome of infants with CDH. Other agents including prostaglandin E1 [89], prostacyclin [90], bosentan [37], and imatinib [91] have been used in the treatment of pulmonary hypertension for CDH and have shown acute improvement in oxygenation index, but all only in small case series. Current use is case-by-case and extrapolated from non-CDH populations in both children and adults.
Despite years of progress in perinatal care, severe congenital diaphragmatic hernia (CDH) remains a clinical challenge. Controversies include almost every facet of clinical care: the definition of severe CDH by prenatal and postnatal criteria, fetal surgical intervention, ventilator management, pulmonary hypertension management, use of extracorporeal membrane oxygenation, surgical considerations, and long-term follow-up. Breakthroughs are likely only possible by sharing of experience, collaboration between institutions and innovative therapies within well-designed multicenter clinical trials.
Contemporary neonatal intensive care management in congenital diaphragmatic hernia: Does this obviate the need for fetal therapy?
2009, Fetal and Maternal Medicine Review
Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension in preclinical models
2021, Pediatric Research
Imatinib relaxes the pulmonary venous bed of guinea pigs
2017, Respiratory Research

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Case reportPlatelet-derived growth factor inhibition—a new treatment of pulmonary hypertension in congenital diaphragmatic hernia?

Abstract

Section snippets

Case report

Discussion

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

Semin Pediatr Surg

J Pediatr Surg

Semin Pediatr Surg

Case report
Platelet-derived growth factor inhibition—a new treatment of pulmonary hypertension in congenital diaphragmatic hernia?