The development of normal lung tissue toxicity after radiation exposure results from multiple changes in cell signaling and communication initiated at the time of the ionizing event. The onset of gross
pulmonary injury is preceded by tissue
hypoxia and chronic oxidative stress. We have previously shown that development of debilitating
lung injury can be mitigated or prevented by administration of
AEOL10150, a potent catalytic
antioxidant, 24h after radiation. This suggests that
hypoxia-mediated signaling pathways may play a role in late
radiation injury, but the exact mechanism remains unclear. The purpose of this study was to evaluate changes in the temporal expression of
hypoxia-associated genes in irradiated mouse lung and determine whether
AEOL10150 alters expression of these genes. A focused oligo array was used to establish a
hypoxia-associated gene expression signature for lung tissue from
sham-irradiated or irradiated mice treated with or without
AEOL10150. Results were further verified by RT-PCR. Forty-four genes associated with metabolism, cell growth, apoptosis,
inflammation, oxidative stress, and extracellular matrix synthesis were upregulated after radiation. Elevated expression of 31 of these genes was attenuated in animals treated with
AEOL10150, suggesting that expression of a number of
hypoxia-associated genes is regulated by early development of oxidative stress after radiation. Genes identified herein could provide insight into the role of hypoxic signaling in radiation
lung injury, suggesting novel therapeutic targets, as well as clues to the mechanism by which
AEOL10150 confers pulmonary radioprotection.