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Improved lung growth and function through hypoxia‐inducible factor in primate chronic lung disease of prematurity
- Source :
- The FASEB Journal. 20:1698-1700
- Publication Year :
- 2006
- Publisher :
- Wiley, 2006.
-
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.
- Subjects :
- Lung Diseases
Male
medicine.medical_specialty
Pathology
Angiogenesis
Neovascularization, Physiologic
Pulmonary compliance
Biochemistry
Neovascularization
chemistry.chemical_compound
Internal medicine
Genetics
medicine
Animals
Enzyme Inhibitors
Lung
Molecular Biology
business.industry
Ductus arteriosus closure
medicine.disease
Respiratory Function Tests
Vascular endothelial growth factor
Treatment Outcome
Endocrinology
medicine.anatomical_structure
Animals, Newborn
Bronchopulmonary dysplasia
Hypoxia-inducible factors
chemistry
Chronic Disease
Premature Birth
Female
Hypoxia-Inducible Factor 1
medicine.symptom
business
Papio
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....afec3ed1f46298609ad6e416c57e0709