title: Biphasic response of checkpoint control proteins in hyperoxia: exposure to lower levels of oxygen induces genome maintenance genes in experimental baboon BPD.
abstract: Breathing high concentrations of oxygen (hyperoxia) causes lung injury and is associated with lung diseases such as bronchopulmonary dysplasia (BPD), respiratory distress syndrome and persistent pulmonary hypertension of the newborns. Hyperoxia (95-100 %O2) causes DNA damage and growth arrest of lung cells and consequently cells die by apoptosis or necrosis. Although supplemental oxygen therapy is clinically important, the level and duration of hyperoxic exposure that would allow lung cells to reenter the cell cycle remains unclear. We hypothesized that cells exposed to lower concentrations of hyperoxia will retain the capacity to enter cell cycle when recovered in room air. We employed varying concentrations of oxygen (21-95 %) to determine the response of lung cells to hyperoxia. Our results indicate that cells were growth arrested and failed to reenter the cell cycle when exposed to greater than 60 % oxygen. Cell cycle checkpoint proteins were increased in a biphasic manner, increasing until 70 % oxygen, but declined in greater than 90 % oxygen. Microarray analysis shows that there is significant decrease in the abundance of Cdks 6-8 and retinoblastoma protein (Rb), p107 and p130 in exposure to 90 % oxygen for 48 h. We further tested the effect of clinically relevant as needed oxygen [(pro-re-nata (prn)] in premature infant (125-days and 140-days) baboon model of BPD. The microarray results show that 6 or 14d PRN oxygen-exposed animals had induced expression of chromosomal maintenance genes (MCMs), genes related to anti-inflammation, proliferation, and differentiation.
authors.affiliation: Department of Anesthesiology, Texas Tech University Health Sciences Center, 3601 4th Street, MS 6598, Lubbock, TX, 79430, USA, kumuda.das@ttuhsc.edu.
authors.forename: Kumuda C
authors.initials: KC
authors.lastname: Das
authors.forename: John D
authors.initials: JD
authors.lastname: Wasnick
mesh_terms: D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018496:Hyperoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010215:Papio
chemical_list: D018797:Cell Cycle Proteins