Singh Vijay K, Serebrenik Artur A, Fatanmi Oluseyi O, Wise Stephen Y, Carpenter Alana D, Janocha Brianna L, Kaytor Michael D
Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Radiat Res. 2023 Mar 1;199(3):294-300. doi: 10.1667/RADE-22-00142.1.
Acute exposure to high dose radiation can cause acute radiation syndrome (ARS), a potentially life-threatening illness. Individuals that survive ARS are at risk of developing the delayed effects of acute radiation exposure, with the lungs being particularly susceptible (DEARE-lung). For individuals at risk of radiation exposure, there are no Food and Drug Administration-approved medical countermeasures (MCMs) for prophylactic or post-exposure use that can prevent or mitigate DEARE-lung. BIO 300 is a novel formulation of synthetic genistein that has been extensively studied as a prophylactic MCM for the hematopoietic subsyndrome of ARS (H-ARS). Here, we used a C57L/J mouse model of total-body irradiation (TBI) to investigate whether prophylactic administration of BIO 300 is able to prevent animals from developing DEARE-lung. Oral and parenteral formulations of BIO 300 administered prior to TBI were compared against standard of care, PEGfilgrastim, administered shortly after radiation exposure, and the combination of oral BIO 300 administered prior to TBI and with PEGfilgrastim administered post-exposure. All animals were exposed to 7.75 Gy cobalt-60 gamma-radiation and the primary endpoint was lung histopathology at 180 days post-TBI. Animals treated with BIO 300 had a significant reduction in the incidence of interstitial lung inflammation compared to vehicle groups for both the oral (0% vs. 47%) and parenteral (13% vs. 44%) routes of administration. Similar results were obtained for the incidence and severity of pulmonary fibrosis in animals treated with oral BIO 300 (incidence, 47% vs. 100% and mean severity score, 0.53 vs. 1.3) and parenteral BIO 300 (incidence, 63% vs. 100% and mean severity score, 0.69 vs. 1.7). PEGfilgrastim alone had no significant effect in reducing the incidence of inflammation or fibrosis compared to vehicle. The combination of oral BIO 300 and PEGfilgrastim significantly reduced the incidence of interstitial inflammation (13% vs. 46%) and the severity of pulmonary fibrosis (mean severity score, 0.93 vs. 1.6). Results in the C57L/J mice were compared to those in CD2F1 mice, which are less prone to lung injury following total-body irradiation. Taken together, these studies indicate that BIO 300 is a promising MCM that is able to prophylactically protect against DEARE-lung.
急性暴露于高剂量辐射可导致急性放射综合征（ARS），这是一种有潜在生命危险的疾病。从ARS中存活下来的个体有发生急性辐射暴露延迟效应的风险，其中肺部尤其易感（延迟效应急性辐射性肺损伤，DEARE - lung）。对于有辐射暴露风险的个体，美国食品药品监督管理局（FDA）尚未批准用于预防或暴露后使用的、可预防或减轻DEARE - lung的医学对策（MCM）。BIO 300是一种新型合成染料木黄酮制剂，已作为ARS造血亚综合征（H - ARS）的预防性MCM进行了广泛研究。在此，我们使用全身照射（TBI）的C57L/J小鼠模型来研究预防性给予BIO 300是否能够防止动物发生DEARE - lung。将TBI前给予的BIO 300口服和肠胃外制剂与辐射暴露后不久给予的标准治疗药物聚乙二醇化非格司亭进行比较，并与TBI前给予口服BIO 300以及暴露后给予聚乙二醇化非格司亭的联合用药进行比较。所有动物均接受7.75 Gy钴 - 60γ辐射，主要终点是TBI后180天的肺组织病理学检查。与赋形剂组相比，接受BIO 300治疗的动物，无论是口服给药途径（0%对47%）还是肠胃外给药途径（13%对44%），间质性肺炎的发生率均显著降低。对于接受口服BIO 300（发生率，47%对100%；平均严重程度评分，0.53对1.3）和肠胃外BIO 300（发生率，63%对100%；平均严重程度评分，0.69对1.7）治疗的动物，肺纤维化的发生率和严重程度也得到了类似结果。与赋形剂相比，单独使用聚乙二醇化非格司亭在降低炎症或纤维化发生率方面没有显著效果。口服BIO 300与聚乙二醇化非格司亭联合使用可显著降低间质性炎症的发生率（13%对46%）和肺纤维化的严重程度（平均严重程度评分，0.93对1.6）。将C57L/J小鼠的结果与CD2F1小鼠的结果进行比较，后者在全身照射后肺损伤的易感性较低。综上所述，这些研究表明BIO 300是一种有前景的MCM，能够预防性保护机体免受DEARE - lung的影响。
