Hypoxia-Inducible Factor-1 Stimulates Postnatal Lung Development but Does Not Prevent O^sub 2^-Induced Alveolar Injury

This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressin...

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Published inAmerican journal of respiratory cell and molecular biology Vol. 52; no. 4; p. 448
Main Authors Tibboel, Jeroen, Groenman, Freek A, Selvaratnam, Johanna, Wang, Jinxia, Tseu, Irene, Huang, Zhen, Caniggia, Isabella, Luo, Daochun, Tuyl, Minke van, Ackerley, Cameron, de Jongste, Johan C, Tibboel, Dick, Post, Martin
Format Journal Article
LanguageEnglish
Published New York American Thoracic Society 01.04.2015
Subjects
Hyperoxia
Hypoxia
Lungs
Proteins
Pulmonary fibrosis
Rodents
Surfactants
Transgenic animals
Vascular endothelial growth factor
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Summary:This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressing a stable, constitutive-active, HIF1α-subunit (HIF-1αΔODD) in the distal lung epithelium. In addition, we compared lung function, histology, and morphometry of neonatal transgenic and wild-type mice subjected to hyperoxia. We found that postnatal lungs of HIF-1αΔODD mice had a greater peripheral vessel density and displayed advanced alveolarization compared with control lungs. Stable HIF-1α expression was associated with increased postnatal expression of angiogenic factors, including vascular endothelial growth factor, angiopoietins 1 and 2, Tie2, and Ephrin B2 and B4. Hyperoxia-exposed neonatal HIF-1αΔODD mice exhibited worse lung function but had similar histological and surfactant abnormalities compared with hyperoxia-exposed wild-type controls. In conclusion, expression of constitutive-active HIF-1α in the lung epithelium was associated with increased postnatal vessel growth via up-regulation of angiogenic factors. The increase in postnatal vasculature was accompanied by enhanced alveolar formation. However, stable HIF-1α expression in the distal lung did not prevent hyperoxia-induced lung injury in neonates but instead worsened lung function.
ISSN:1535-4989