Advances in neonatal critical care have greatly improved the survival of preterm infants but the long-term complications of prematurity, including Bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. While Vascular Endothelial Growth Factor (VEGF) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in BPD patients.
To test whether nanoparticle delivery of proangiogenic transcription factors FOXM1 or FOXF1, both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.
Newborn mice were exposed to 75% O2 for 7 days of life before being returned to room air. On postnatal day 2, polyethylenimine-(5) myristic acid/ poly(ethylene glycol)-oleic acid/ cholesterol (PEI600-MA5/PEG-OA/Cho) nanoparticles containing non-integrating expression plasmids with Foxm1 or Foxf1 cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry and the Flexivent small animal ventilator.
The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification and preserved lung function in mice reaching adulthood.
Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.