Related Experiment Video
Updated: Aug 7, 2026
Development of a Neonatal Piglet Acute Lung Injury Model Recreating the Early Environment of Preterm Infant Lungs
Published on: October 31, 2025
Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity
Tiina M Asikainen1, Ling-Yi Chang, Jacqueline J Coalson
1Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Rm. J-318, Denver, Colorado 80206, USA.
Insights
Hypoxia-inducible factor (HIF) stimulation via PHD inhibition improved lung growth and function in preterm baboons with bronchopulmonary dysplasia (BPD). Treatment recovered alveolar surface area and enhanced oxygenation, offering a potential therapy for this chronic lung disease.
Area of Science:
- Neonatal Medicine
- Pulmonary Medicine
- Developmental Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants, characterized by impaired lung vascular and airway development.
- Hypoxia-inducible factors (HIFs) play a crucial role in angiogenesis and lung development.
- Previous in vitro studies demonstrated that inhibiting prolyl hydroxylase domain-containing proteins (PHDs) activates HIFs and promotes vascular endothelial growth factor (VEGF)-dependent angiogenesis.
Purpose of the Study:
- To investigate whether activating HIFs by inhibiting PHDs improves lung growth and function in a preterm neonate model of BPD in vivo.
- To assess the therapeutic potential of PHD inhibitors for BPD.
Main Methods:
- Preterm baboons (equivalent to 27 human gestational weeks) were treated with FG-4095, a PHD inhibitor, for 14 days.
- Lung structure, gas exchange, lung mechanics, and specific biochemical markers were evaluated.
Main Results:
- FG-4095 treatment significantly recovered 77% of the diminished total alveolar surface area compared to untreated controls.
- Improved oxygenation and lung compliance were observed in FG-4095 treated neonates, indicating functional benefits.
- Increased spontaneous closure of the ductus arteriosus was noted, potentially reducing pulmonary to systemic blood flow ratio.
Conclusions:
- Stimulation of HIFs by PHD inhibition effectively ameliorates the pathological and physiological consequences of BPD in a preterm baboon model.
- This approach represents a promising therapeutic strategy for managing BPD and improving long-term respiratory outcomes in preterm infants.
Abstract:
Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting preterm neonates, is associated with significant childhood and adult health problems. Histopathologic features of BPD include impaired vascular and distal airway development. We previously showed that activation of hypoxia-inducible factors (HIFs) by inhibition of prolyl hydroxylase domain-containing proteins (PHDs) is feasible and that it stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis in vitro. We tested the hypothesis that enhancement of angiogenesis by activation of HIFs improves lung growth and function in prematurely born neonates in vivo. Preterm baboons (125 day+14 day pro re nata O2 model, corresponding to 27 human gestational weeks) were treated for 14 days with intravenous (i.v.) FG-4095, a PHD inhibitor. Notably, 77% of diminished total alveolar surface area in untreated controls was recovered by FG-4095 treatment. Functional significance of the structural changes was indicated by improved oxygenation and lung compliance in FG-4095-treated newborns. Surfactant proteins B and C and saturated phosphatidylcholine were unchanged. Incidence of spontaneous ductus arteriosus closure was increased, likely contributing to lower ratio of pulmonary to systemic blood flow in FG-4095 group. These findings indicate that HIF stimulation by PHD inhibition ameliorates pathological and physiological consequences of BPD.
