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

Am J Respir Crit Care Med. 2020 Oct 15;202(8):1146-1158. doi: 10.1164/rccm.202003-0601OC.


Rationale: Antenatal inflammation with placental dysfunction is strongly associated with high bronchopulmonary dysplasia (BPD) risk in preterm infants. Whether antenatal or postnatal HIF (hypoxia-inducible factor) augmentation can preserve lung structure and function and prevent pulmonary hypertension after intrauterine inflammation is controversial.Objectives: To determine whether antenatal or postnatal prolyl-hydroxylase inhibitor (PHi) therapy increases lung HIF expression, preserves lung growth and function, and prevents pulmonary hypertension in a rat model of chorioamnionitis-induced BPD caused by antenatal inflammation.Methods: Endotoxin (ETX) was administered to pregnant rats by intraamniotic injection at Embryonic Day 20, and pups were delivered by cesarean section at Embryonic Day 22. Selective PHi drugs, dimethyloxalylglycine or GSK360A, were administered into the amniotic space at Embryonic Day 20 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, VEGF (vascular endothelial growth factor), and eNOS (endothelial nitric oxide synthase) protein contents. At Day 14, lung function was assessed, and tissues were harvested to determine alveolarization by radial alveolar counts, pulmonary vessel density, and right ventricle hypertrophy (RVH).Measurements and Main 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 upregulates lung HIF-1a, HIF-2a, VEGF, and eNOS expression after ETX exposure.Conclusions: HIF augmentation improves 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: bronchopulmonary dysplasia; endotoxin; hypoxia-inducible factors; prolyl-hydroxylase inhibitors; pulmonary hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Bronchopulmonary Dysplasia / drug therapy*
  • Bronchopulmonary Dysplasia / metabolism
  • Bronchopulmonary Dysplasia / pathology
  • Disease Models, Animal
  • Endotoxins / adverse effects
  • Endotoxins / pharmacology
  • Female
  • Hypoxia-Inducible Factor 1 / drug effects
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Immunohistochemistry
  • In Vitro Techniques
  • Injections, Intralesional
  • Lung / drug effects*
  • Lung / embryology
  • Peptide PHI / pharmacology*
  • Pregnancy
  • Pregnancy, Animal*
  • Prenatal Care
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / growth & development
  • Pulmonary Circulation / drug effects
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reference Values
  • Respiratory Function Tests
  • Tissue Culture Techniques


  • Amino Acids, Dicarboxylic
  • Endotoxins
  • Hypoxia-Inducible Factor 1
  • Peptide PHI
  • oxalylglycine