Loss of Gadd45a does not modify the pulmonary response to oxidative stress.
It is well established that exposure to high levels of oxygen (hyperoxia) injures and kills microvascular endothelial and alveolar type I epithelial cells. In contrast, significant death of airway and type II epithelial cells is not observed at mortality, suggesting that these cell types may express genes that protect against oxidative stress and damage. During a search for genes induced by hyperoxia, we previously reported that airway and alveolar type II epithelial cells uniquely express the growth arrest and DNA damage (Gadd)45a gene. Because Gadd45a has been implicated in protection against genotoxic stress, adult Gadd45a (+/+) and Gadd45a (-/-) mice were exposed to hyperoxia to investigate whether it protected epithelial cells against oxidative stress. During hyperoxia, Gadd45a deficiency did not affect loss of airway epithelial expression of Clara cell secretory protein or type II epithelial cell expression of pro-surfactant protein C. Likewise, Gadd45a deficiency did not alter recruitment of inflammatory cells, edema, or overall mortality. Consistent with Gadd45a not affecting the oxidative stress response, p21(Cip1/WAF1) and heme oxygenase-1 were comparably induced in Gadd45a (+/+) and Gadd45a (-/-) mice. Additionally, Gadd45a deficiency did not affect oxidative DNA damage or apoptosis as assessed by oxidized guanine and terminal deoxyneucleotidyl transferase-mediated dUTP nick-end labeling staining. Overexpression of Gadd45a in human lung adenocarcinoma cells did not affect viability or survival during exposure, whereas it was protective against UV-radiation. We conclude that increased tolerance of airway and type II epithelial cells to hyperoxia is not attributed solely to expression of Gadd45a.
Roper
Jason M
JM
Departments of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
Gehen
Sean C
SC
Staversky
Rhonda J
RJ
Hollander
M Christine
MC
Fornace
Albert J
AJ
O'Reilly
Michael A
MA
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D004487:Edema / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006720:Homozygote; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D055370:Lung Injury; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D010100:Oxygen / Q000008:administration & dosage; D011650:Pulmonary Alveoli / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014598:Uteroglobin / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010100:Oxygen; D014598:Uteroglobin; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C499072:Gadd45a protein, mouse; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse