title: Hyperoxic ventilated premature baboons have increased p53, oxidant DNA damage and decreased VEGF expression.
abstract: Hyperoxia is implicated in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. High levels of supplemental oxygen can result in microvascular endothelial cell death and may disrupt lung development. In postnatal animals, hyperoxia inhibits expression of vascular endothelial growth factor (VEGF), which is required for normal vascular development. A potential mechanism of oxygen effects on VEGF is induction of p53, a transcription factor that represses VEGF gene transcription. Oxidant DNA damage can increase p53. We used a moderately premature baboon model of hyperoxia to examine p53, oxidant DNA damage, and VEGF expression. Fetal baboons delivered at 140 d of gestation (75% of term) were ventilated with 100% oxygen or oxygen as needed for 6 or 10 d. Lungs from the 10-d 100% oxygen animals had increased nuclear p53, compared with the oxygen as needed animals. The mechanism of increased p53 was probably related to oxidant DNA damage, which was documented by increased oxidized guanine. Dual fluorescent confocal microscopy found increased oxidized guanine in mitochondrial DNA of distal lung epithelial cells. Distal epithelial cell VEGF expression was decreased and p21, another downstream target of p53, was increased in the distal epithelium of the hyperoxic animals. These data show that p53 is induced in hyperoxic fetal lung epithelium and are consistent with p53 repression of VEGF expression in these cells. The findings suggest that oxidant DNA damage may be a mechanism of increased p53 in hyperoxic fetal lung.
authors.affiliation: Division of Neonatology, Children's Research Center, Pulmonary Biology and Disease Program, University of Rochester School of Medicine, Rochester, NY 14642, USA. William_Maniscalco@URMC.Rochester.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Maniscalco
authors.forename: Richard H
authors.initials: RH
authors.lastname: Watkins
authors.forename: Jason M
authors.initials: JM
authors.lastname: Roper
authors.forename: Rhonda
authors.initials: R
authors.lastname: Staversky
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Reilly
mesh_terms: D000818:Animals; D004249:DNA Damage; D015870:Gene Expression; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D010215:Papio; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D016877:Oxidants; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D006151:Guanosine; C046215:8-hydroxyguanosine