10-Nitro-oleic acid improves survival following gamma irradiation and modulates hematopoietic and intestinal responses

Abstract

Acute radiation syndrome remains a major consequence of high-dose ionizing radiation exposure, and effective pharmacological countermeasures are limited. Nitro-fatty acids possess anti-inflammatory and cytoprotective properties, suggesting potential effectiveness in radiation injury. Here, we investigated the radioprotective effects of 10-nitro-oleic acid (10-NO2OA) in mouse models of total body irradiation (TBI). C57BL/6 mice were exposed to either sublethal (4 Gy) or LD50-level (7.5 Gy) gamma irradiation and treated with 10-NO2OA according to pre-irradiation, post-irradiation, or combined treatment regimens. Survival, hematological responses, bone marrow cells (BMCs)/colony-forming units (CFU), plasma granulocyte colony-stimulating factor (G-CSF), NRF2-responsive signaling, and intestinal responses were evaluated. Administration of 10-NO2OA before and after irradiation significantly improved 30-day survival following 7.5 Gy TBI (57% vs. 20% in vehicle-treated controls). In contrast, post-irradiation treatment alone was ineffective, whereas pre-irradiation treatment alone produced a non-significant trend toward improved survival. The protective effect was absent in BALB/c mice, indicating strain dependence. Although 10-NO2OA did not prevent long-term radiation-induced cytopenia, it increased neutrophil and platelet counts, elevated plasma G-CSF levels shortly after irradiation, and transiently enhanced BMC counts. In irradiated BMCs, 10-NO2OA activated NRF2-responsive gene expression in vitro and in vivo. Exploratory intestinal analyses revealed improved macroscopic appearance and partial restoration of irradiation-suppressed cytokine and growth factor production. In conclusion, 10-NO2OA improves survival following LD50-level gamma irradiation and is associated with modulation of hematopoietic, cytoprotective, and intestinal responses. These findings identify 10-NO2OA as a promising candidate radioprotective agent and support a multifactorial mechanism of action.