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Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss induced by radiation damage to the GI tract. We report that prolyl hydroxylase inhibition by genetic knockout or pharmacologic inhibition of all PHD (prolyl hydroxylase domain) isoforms by the small-molecule dimethyloxallyl glycine (DMOG) increases hypoxia-inducible factor (HIF) expression, improves epithelial integrity, reduces apoptosis, and increases intestinal angiogenesis, all of which are essential for radioprotection. HIF2, but not HIF1, is both necessary and sufficient to prevent radiation-induced GI toxicity and death. Increased vascular endothelial growth factor (VEGF) expression contributes to the protective effects of HIF2, because inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.

Original publication

DOI

10.1126/scitranslmed.3008523

Type

Journal article

Journal

Sci Transl Med

Publication Date

14/05/2014

Volume

6

Keywords

Amino Acids, Dicarboxylic, Animals, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, Body Weight, Cell Line, Tumor, Chelating Agents, Gastrointestinal Tract, Gene Expression Regulation, Hematocrit, Heterozygote, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Knockout, Prolyl-Hydroxylase Inhibitors, Protein Isoforms, Protein Structure, Tertiary, Radiation Injuries, Vascular Endothelial Growth Factor A