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Published ahead of print on November 7, 2003, doi:10.1165/rcmb.2003-0049OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 5, May 2004, 635-640

A more recent version of this article appeared on May 1, 2004
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Submitted on February 12, 2003
Revised on November 7, 2003

The Effect of Neonatal Hyperoxia on the Lung of p21Waf1/Cip1/Sdi1 Deficient Mice

Sharon A McGrath-Morrow1*, Cecilia Cho1, Shawn Soutiere2, Wayne Mitzner2, and Rubin Tuder3

1 Pediatrics, Johns Hopkins University, Baltimore, MD, USA, 2 Physiology, Johns Hopkins University, Baltimore, MD, USA, 3 Pathology, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. 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. p21Waf1/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 wildtype (p21+/+) mice in 85-90% oxygen (O2) for four days. We found that newborn p21-/- mice exposed to O2 had decreased survival in hyperoxia compared to p21+/+ mice (p<.01). At two and six weeks post 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 six weeks 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 two and six weeks of age, p21-/- O2 lung had significantly more oxidative stress then 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 since it is associated with lower levels of oxidative stress and increased oxidative stress may contribute to alveolar growth abnormalities in the p21-/- O2 lung.




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