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The Effect of Neonatal Hyperoxia on the Lung of p21^{Waf1/Cip1/Sdi1}-Deficient Mice

Department of Pediatrics, Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Medical Institutions; Department of Physiology; and Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Address correspondence to: Dr. Sharon A. McGrath-Morrow, Department of Pediatrics, Johns Hopkins Hospital, Park 316/600 N. Wolfe St., Baltimore, MD 21287-2533. E-mail: smorrow{at}jhmi.edu

Hyperoxia is an important factor in the development of bronchopulmonary dysplasia and is associated with growth arrest and impaired alveolar septal development in the neonatal lung. p21^{Waf1/Cip1/Sdi1} (p21), a cyclin-dependent kinase inhibitor, acts as a checkpoint regulator in the cell cycle during periods of stress and is induced in neonatal lung during hyperoxia exposure. To determine if p21 protects against lung injury during neonatal lung development, we placed newborn p21 knockout (p21^–/–) and p21 wild-type (p21^+/+) mice in 85–90% O₂ for 4 d. We found that newborn p21^–/– mice exposed to O₂ had decreased survival in hyperoxia compared with p21^+/+ mice (P < 0.01). At 2 and 6 wk after exposure to neonatal hyperoxia, p21^–/– O₂ lung had significantly larger alveoli then p21^–/– control lung, as assessed by mean alveolar size and mean linear intercept. Pulmonary function tests at 6 wk demonstrated increased lung volume in both p21^–/– and p21^+/+ O₂ mice consistent with altered lung growth from neonatal exposure to hyperoxia. Antibodies to nitrotyrosine, a marker for oxidative stress revealed that at 2 and 6 wk of age, p21^–/– O₂ lung had significantly more oxidative stress than p21^–/– and p21^+/+ control and p21^+/+ O₂ lung. We therefore conclude that p21 confers some additional protection to the lung during exposure to neonatal hyperoxia. Furthermore, p21 may be important during recovery from lung injury because it is associated with lower levels of oxidative stress and increased oxidative stress may contribute to alveolar growth abnormalities in the p21^–/– O₂ lung.

Abbreviations: ataxia telangiectasia, AT • bronchopulmonary dysplasia, BPD • diaminobenzidine, DAB • day of life, DOL • mean alveolar size, MAS • mean linear intercept, MLI • pulmonary function test, PFT

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