Hyperoxia impairs postnatal alveolar epithelial development via NADPH oxidase in newborn mice.
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 p47(phox) subunit null (p47(phox-/-)) mice to air or acute hyperoxia (95% O(2)) for up to 11 days. Hyperoxia-induced pulmonary neutrophil influx was similar in wild-type and p47(-/-) mice at postnatal days (P) 7 and 11. Macrophages were decreased in wild-type hyperoxia-exposed mice compared with p47(phox-/-) 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 p21(cip/waf) in type II cells, which was induced in 95% O(2)-exposed wild-type mice, but significantly less in p47(phox-/-) littermates at P7. Despite partial preservation of type II cell proliferation, deletion of p47(phox) 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 vs. p47(phox-/-) mice at P11. Since we found that p47(phox) 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.
Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Neonatal-Perinatal Research Institute, Durham, North Carolina 27710, USA. auten@duke.edu
Richard L
RL
Auten
S Nicholas
SN
Mason
Kathryn M
KM
Auten
Mulugu
M
Brahmajothi
D000375:Aging / Q000187:drug effects / Q000473:pathology; D000388:Air; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D017353:Gene Deletion; D018496:Hyperoxia / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D011014:Pneumonia / Q000201:enzymology / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology*; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D016019:Survival Analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D037721:Pulmonary Surfactant-Associated Protein C; C002744:3-nitrotyrosine; D014443:Tyrosine; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D010100:Oxygen