Deferoxamine Improves Alveolar and Pulmonary Vascular Development by Upregulating Hypoxia-inducible Factor-1α in a Rat Model of Bronchopulmonary Dysplasia.
Fetal lung development normally occurs in a hypoxic environment. Hypoxia-inducible factor (HIF)-1α 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-1α 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-1α 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-1α was significantly upregulated in the lungs of BPD rats treated with DFX. DFX was also found to induce HIF-1α in human small airway epithelial cells and to promote the expression of HIF-1α target genes. Our data suggest that DFX induces and activates HIF-1α, thereby improving alveolarization and vascular distribution in the lungs of rats with BPD.
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea. ; Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.
Chang Won
CW
Choi
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.
Juyoung
J
Lee
Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea.
Hyun Ju
HJ
Lee
Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
Hyoung-Sook
HS
Park
Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
Yang-Sook
YS
Chun
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea. ; Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.
Beyong Il
BI
Kim
D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003676:Deferoxamine / Q000008:administration & dosage*; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D011667:Pulmonary Veins / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003676:Deferoxamine
Alveolarization; Bronchopulmonary Dysplasia; Deferoxamine; Hypoxia-Inducible Factor