Exacerbation of Mild Hypoxia on Acute Radiation Syndrome and Subsequent Mortality.

Mild hypoxia induced by 20% hemorrhage results in increases in few cytokine concentrations and sclerostin levels in blood, but shows no changes in bone formation, bone marrow cellularity, and gastrointestinal (GI) integrity and no systemic bacterial infection as well as no subsequent mortality. On the other hand, severe hypoxia induced by 40% hemorrhage causes significant increases in most cytokine concentrations, GI injury, lung injury, systemic bacterial infection, cellular ATP reduction and subsequent mortality. The severe hypoxia drastically damages GI and lung morphology, elevates cytokine concentrations in blood and increases inducible nitric oxide synthase (iNOS) expression in cells that is mediated by transcription factors NF-κB/NF-IL6, subsequently producing free radicals that disrupt mitochondria. ATP depletion, p53 phosphorylation, and caspase-3 activation are found, suggesting cell apoptosis. As a result, mortality occurs. However, when mild hypoxia follows ionizing radiation, the mild hypoxia significantly enhances radiation-induced mortality and acute radiation syndrome, including injury of bone marrow, GI, kidney, and lung. The synergism also occurs at the molecular level, resulting in alteration of microRNAs, amplification of iNOS expression, cytokine increases, sepsis, and ATP depletion. This is the first demonstration of synergistic effects between mild hypoxia and ionizing radiation.