Submitted on April 2, 2009
Revised on April 28, 2009
Accepted on April 28, 2009
Hyperoxia Impairs Postnatal Alveolar Epithelial Development via NADPH oxidase in Newborn Mice
Richard L. Auten1*, Stanley Nicholas Mason1, Kathryn M. Auten1, and Mulugu Brahmajothi1
1 Duke University Medical Center
* To whom correspondence should be addressed. E-mail: auten{at}duke.edu.
Hyperoxia disrupts postnatal lung development in part through inducing inflammation. To determine the contribution of leukocyte-derived reactive oxygen species, we exposed newborn wild-type and NADPH oxidase p47phox subunit null (p47phox-/-) mice to air or acute hyperoxia (95%O2) up to 11 days. Hyperoxia induced pulmonary neutrophil influx was similar in wild-type and p47-/- mice at postnatal day (P) 7 and 11. Macrophages were decreased in wild-type hyperoxia-exposed mice compared with p47phox -/- mice at P11. Hyperoxia impaired type II alveolar epithelial cell and bronchiolar epithelial cell proliferation, but depression of type II cell proliferation was significantly less in p47-/- mice at P3 and P7, when inflammation was minimal. We found reciprocal results for the expression of the cell-cycle inhibitor p21cip/waf in type II cells, which was induced in 95%O2-exposed wild-type mice, but significantly less in p47 phox -/- littermates at P7. Despite partial preservation of type II cell proliferation, deletion of p47phox did not prevent the major adverse effects of hyperoxia on alveolar development estimated by morphometry at P11, but hyperoxia-impairment of elastin deposition at alveolar septal crests was significantly worse in wild-type v. p47phox -/- mice at P11. Since we found that p47phox is expressed in a subset of alveolar epithelial cells, its deletion may protect postnatal type II alveolar epithelial proliferation from hyperoxia through effects on epithelial as well as phagocyte-generated superoxide.
