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Int. J. Mol. Sci. 2016, 17(6), 953; doi:10.3390/ijms17060953

Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel

1
Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA
2
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
3
The National Aeronautics and Space Administration (NASA) Johnson Space Center, Houston, TX 77058, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Terrence Piva
Received: 8 February 2016 / Revised: 6 June 2016 / Accepted: 9 June 2016 / Published: 16 June 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [4340 KB, uploaded 16 June 2016]   |  

Abstract

Spaceflight occasionally requires multiple extravehicular activities (EVA) that potentially subject astronauts to repeated changes in ambient oxygen superimposed on those of space radiation exposure. We thus developed a novel in vitro model system to test lung cell damage following repeated exposure to radiation and hyperoxia. Non-tumorigenic murine alveolar type II epithelial cells (C10) were exposed to >95% O2 for 8 h only (O2), 0.25 Gy ionizing γ-radiation (IR) only, or a double-hit combination of both challenges (O2 + IR) followed by 16 h of normoxia (ambient air containing 21% O2 and 5% CO2) (1 cycle = 24 h, 2 cycles = 48 h). Cell survival, DNA damage, apoptosis, and indicators of oxidative stress were evaluated after 1 and 2 cycles of exposure. We observed a significant (p < 0.05) decrease in cell survival across all challenge conditions along with an increase in DNA damage, determined by Comet analysis and H2AX phosphorylation, and apoptosis, determined by Annexin-V staining, relative to cells unexposed to hyperoxia or radiation. DNA damage (GADD45α and cleaved-PARP), apoptotic (cleaved caspase-3 and BAX), and antioxidant (HO-1 and Nqo1) proteins were increased following radiation and hyperoxia exposure after 1 and 2 cycles of exposure. Importantly, exposure to combination challenge O2 + IR exacerbated cell death and DNA damage compared to individual exposures O2 or IR alone. Additionally levels of cell cycle proteins phospho-p53 and p21 were significantly increased, while levels of CDK1 and Cyclin B1 were decreased at both time points for all exposure groups. Similarly, proteins involved in cell cycle arrest was more profoundly changed with the combination challenges as compared to each stressor alone. These results correlate with a significant 4- to 6-fold increase in the ratio of cells in G2/G1 after 2 cycles of exposure to hyperoxic conditions. We have characterized a novel in vitro model of double-hit, low-level radiation and hyperoxia exposure that leads to oxidative lung cell injury, DNA damage, apoptosis, and cell cycle arrest. View Full-Text
Keywords: cell cycle; DNA damage; extravehicular activity; hyperoxia; ionizing radiation; lung cell injury; oxidative stress; reactive oxygen species; and space exploration cell cycle; DNA damage; extravehicular activity; hyperoxia; ionizing radiation; lung cell injury; oxidative stress; reactive oxygen species; and space exploration
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MDPI and ACS Style

Pietrofesa, R.A.; Velalopoulou, A.; Lehman, S.L.; Arguiri, E.; Solomides, P.; Koch, C.J.; Mishra, O.P.; Koumenis, C.; Goodwin, T.J.; Christofidou-Solomidou, M. Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel. Int. J. Mol. Sci. 2016, 17, 953.

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