Deferoxamine Improves Alveolar and Pulmonary Vascular Development by Upregulating Hypoxia-inducible Factor-1alpha in a Rat Model of Bronchopulmonary Dysplasia

ABSTRACT

Fetal lung development normally occurs in a hypoxic environment. Hypoxia-inducible factor (HIF)-1alpha is robustly induced under hypoxia and transactivates many genes that are essential for fetal development. Most preterm infants are prematurely exposed to hyperoxia, which can halt hypoxia-driven lung maturation. We were to investigate whether the HIF-1alpha inducer, deferoxamine (DFX) can improve alveolarization in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was produced by intra-amniotic lipopolysaccharide (LPS) administration and postnatal hyperoxia (85% for 7 days), and DFX (150 mg/kg/d) or vehicle was administered to rat pups intraperitoneally for 14 days. On day 14, the rat pups were sacrificed and their lungs were removed and examined. A parallel in vitro study was performed with a human small airway epithelial cell line to test whether DFX induces the expression of HIF-1alpha and its target genes. Alveolarization and pulmonary vascular development were impaired in rats with BPD. However, DFX significantly ameliorated these effects. Immunohistochemical analysis showed that HIF-1alpha was significantly upregulated in the lungs of BPD rats treated with DFX. DFX was also found to induce HIF-1alpha in human small airway epithelial cells and to promote the expression of HIF-1alpha target genes. Our data suggest that DFX induces and activates HIF-1alpha, thereby improving alveolarization and vascular distribution in the lungs of rats with BPD.