Abstract
Background: Patients with congenital diaphragmatic hernia (CDH) have a short postnatal period of ventilatory stability called the honeymoon period, after which changes in pulmonary vascular reactivity result in pulmonary hypertension. However, the mechanisms involved are still unknown. The aim of this study was to evaluate mechanical ventilation's effect in the honeymoon period on VEGF, VEGFR-1/2 and eNOS expression on experimental CDH in rats.Materials and Methods: Neonates whose mothers were not exposed to nitrofen formed the control groups (C) and neonates with left-sided defects formed the CDH groups (CDH). Both were subdivided into non-ventilated and ventilated for 30, 60, and 90 min (n = 7 each). The left lungs (n = 4) were evaluated by immunohistochemistry of the pulmonary vasculature (media wall thickness), VEGF, VEGFR-1/2 and eNOS. Western blotting (n = 3) was performed to quantify the expression of VEGF, VEGFR-1/2 and eNOS.Results: CDH had lower biometric parameters than C. Regarding the pulmonary vasculature, C showed a reduction in media wall thickness with ventilation, while CDH presented reduction with 30 min and an increase with the progression of the ventilatory time (honeymoon period). CDH and C groups showed different patterns of VEGF, VEGFR-1/2 and eNOS expressions. The receptors and eNOS findings were significant by immunohistochemistry but not by western blotting, while VEGF was significant by western blotting but not by immunohistochemistry.Conclusion: VEGF, its receptors and eNOS were altered in CDH after mechanical ventilation. These results suggest that the VEGF-NO pathway plays an important role in the honeymoon period of experimental CDH.
Highlights
Congenital diaphragmatic hernia (CDH) has an incidence of 1.09–2.67:10,000 live births [1,2,3], with a survival rate of 61% [4]
Neonates were separated into eight groups with n = 7 neonates in each: non-ventilated controls (C); controls ventilated for 30 min (C30), 60 min (C60), or 90 min (C90), all from dams that were not exposed to nitrofen; non-ventilated neonates with CDH (CDH), and neonates with CDH ventilated for 30 min (CDH30), 60 min (CDH60) and 90 min (CDH90), all with left side defects
Newborns with CDH had lower birth weight, lower lung weight and lower lung to body weight ratios, showing significant pulmonary hypoplasia compared to controls (Figure 1)
Summary
Congenital diaphragmatic hernia (CDH) has an incidence of 1.09–2.67:10,000 live births [1,2,3], with a survival rate of 61% [4]. Newborns with CDH often experience a honeymoon period during which they have adequate oxygenation. The mechanisms involved in this period are not clearly understood, but they could shed light on potential therapeutic strategies to improve oxygenation and ventilation in CDH. Vascular endothelial growth factor (VEGF) and nitric oxide (NO) play a central role in the pathogenesis of PH in CDH. Patients with congenital diaphragmatic hernia (CDH) have a short postnatal period of ventilatory stability called the honeymoon period, after which changes in pulmonary vascular reactivity result in pulmonary hypertension. The aim of this study was to evaluate mechanical ventilation’s effect in the honeymoon period on VEGF, VEGFR-1/2 and eNOS expression on experimental CDH in rats
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