title: Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity.
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.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Rm. J-318, Denver, Colorado 80206, USA.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Asikainen
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Chang
authors.forename: Jacqueline J
authors.initials: JJ
authors.lastname: Coalson
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Schneider
authors.forename: Nahid S
authors.initials: NS
authors.lastname: Waleh
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: John M
authors.initials: JM
authors.lastname: Shannon
authors.forename: Vicki T
authors.initials: VT
authors.lastname: Winter
authors.forename: Peter
authors.initials: P
authors.lastname: Grubb
authors.forename: Ronald I
authors.initials: RI
authors.lastname: Clyman
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Yoder
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism* / Q000502:physiology; D008168:Lung / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010215:Papio; D047928:Premature Birth; D012129:Respiratory Function Tests; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1