Revisiting the Role for HIF Stabilizers in Bronchopulmonary Dysplasia

The authors looks on the study of Hirsch and colleagues who provide additional preclinical evidence underscoring the therapeutic efficacy of HIF stabilization in attenuation and prevention of BPD. By combining intraamniotic injection of Escherichia coli endotoxin (mimicking human chorioamnionitis) and preterm delivery, the authors sought to determine whether prenatal stressors are sufficient to compromise alveolar development in the offspring and whether this anticipated defect could be rescue by activation of HIFs. As the authors anticipated, reduced expression of HIF-1 and HIF-2 and their target genes (VEGF and endothelial nitric oxide synthase) decreased pulmonary vascular density, increased airspace enlargement, and increased right ventricular hypertrophy (RVH) were noticed in 14-day-old pups maternally exposed to endotoxin. Remarkably, all of these abnormalities were partially or completely cancelled on antenatal or postnatal inhibition of PHDs with dimethyloxalylglycine or GSK360A. The group demonstrated that postnatal supplementation in IGF-1 (insulin-like growth factor 1) and its binding protein IGFBP-3, a PHD-independent positive regulator of HIF-1 expression, significantly preserves lung structure and function and prevents RVH in three different animal models of BPD, including intraamniotic injection of endotoxin. Furthermore, the authors emphasized that the findings validate promising results of a phase 2 randomized controlled trial (NCT 01096784) reporting a decrease in the occurrence of severe BPD in extremely preterm infants receiving continuous intravenous infusion of IGF-1/IGFBP-3.