Perinatal Hypoxia-Inducible Factor Stabilization Preserves Lung Alveolar and Vascular Growth in Experimental BPD

Background: Antenatal inflammation with placental dysfunction is strongly associated with high BPD risk in preterm infants. Whether antenatal or postnatal HIF augmentation can preserve lung structure and function and prevent pulmonary hypertension (PH) after intrauterine inflammation is controversial.

Objective: To determine if antenatal or postnatal prolyl-hydroxylase inhibitor (PHi) therapy increases lung HIF expression, preserves lung growth and function and prevents PH in a rat model of CA-induced BPD caused by antenatal inflammation.

Methods: Endotoxin was administered to pregnant rats by intra-amniotic (IA) injection at embryonic day 20 and pups were delivered by cesarean-section at E22. Selective PHi drugs, dimethyloxalylglycine (DMOG) or GSK360A (GSK), were administered into the amniotic space at E20 or after birth by intraperitoneal injection for 2 weeks. Placentas and lung tissue were collected at birth for morphometric and western blot measurements of HIF-1a, HIF-2a, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) protein contents. At day 14, lung function was assessed, and tissues were harvested to determine alveolarization by radial alveolar counts(RAC) and pulmonary vessel density(PVD) and right ventricular hypertrophy(RVH).

Results: Antenatal PHi therapy preserves lung alveolar and vascular growth and lung function and prevents RVH after intrauterine ETX exposure. Antenatal administration of PHi markedly up-regulates lung HIF-1a, HIF-2a, VEGF and eNOS expression after ETX exposure.

Conclusions: HIF augmentation improve lung structure and function, prevents RVH and improves placental structure following antenatal ETX exposure. We speculate that antenatal or postnatal PHi therapy may provide novel strategies to prevent BPD due to antenatal inflammation.

Keywords: Hypoxia-inducible factors; bronchopulmonary dysplasia; chorioamnionitis; placenta; prolyl hydroxylase inhibitors.