Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity

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...

Full description

Saved in:
Bibliographic Details
Published in:The FASEB journal 2006-08, Vol.20 (10), p.1698-1700
Main Authors: Asikainen, Tiina M, Chang, Ling-Yi, Coalson, Jacqueline J, Schneider, Barbara K, Waleh, Nahid S, Ikegami, Machiko, Shannon, John M, Winter, Vicki T, Grubb, Peter, Clyman, Ronald I, Yoder, Bradley A, Crapo, James D, White, Carl W
Format: Article
Language:English
Subjects:
alveolization
angiogenesis
Animals
Animals, Newborn
bronchopulmonary dysplasia
Chronic Disease
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - pharmacology
Female
Hypoxia-Inducible Factor 1 - metabolism
Hypoxia-Inducible Factor 1 - physiology
Lung - growth & development
Lung - pathology
Lung - physiopathology
lung development
Lung Diseases - drug therapy
Lung Diseases - etiology
Male
Neovascularization, Physiologic - drug effects
Papio
Premature Birth
preterm neonate
Respiratory Function Tests
Treatment Outcome
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.--Asikainen, T. M., Chang, L.-Y., Coalson, J. J., Schneider, B. K., Waleh, N. S., Ikegami, M., Shannon, J. M., Winter, V. T., Grubb, P., Clyman, R. I., Yoder, B. A., Crapo, J. D., White, C. W. Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.06-5887fje