PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model.
PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model.
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PEG-G-CSF和L-citrulline联合疗法可缓解小鼠模型中皮肤伤口的辐射损伤。
DOI：
10.1667/rade-20-00151.1
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发表时间：
2021-07-01
影响因子：
3.4
通讯作者：
Xiao M
中科院分区：
文献类型：
--
作者：
Wang L;Zhai M;Lin B;Cui W;Hull L;Li X;Anderson MN;Smith JT;Umali MV;Jiang S;Kiang JG;Xiao M
辐射联合损伤（RCI，辐射暴露加上其他形式的损伤，如烧伤、创伤、出血、爆炸、外伤和/或败血症）约占核爆炸损伤的 65%，与单独的辐射损伤相比，大大增加了发病和死亡的风险。迄今为止，美国食品和药物管理局 (FDA) 尚未批准针对 RCI 的对策。目前，三种白细胞生长因子（Neupogen®、Neulasta® 和 Leukine®）已被 FDA 批准用于缓解造血急性辐射综合征。然而，这些粒细胞集落刺激因子 (G-CSF) 和粒细胞巨噬细胞集落刺激因子 (GM-CSF) 产品未能提高 RCI 后小鼠 30 天的存活率，这表明 RCI 的生物学机制比辐射损伤更复杂。在当前的研究中，在 RCI 小鼠模型中评估了使用聚乙二醇化 (PEG)-G-CSF (Neulasta) 和 L-瓜氨酸的联合疗法的缓解效果。 L-瓜氨酸是一种中性α-氨基酸，可改善心血管疾病中的血管内皮功能。照射后第 1、8 和 15 天皮下注射 3 剂 1 mg/kg 的 PEG-G-CSF，并补充口服 L-瓜氨酸 (1 g/kg)，从照射后第 1 天到第 21 天每天一次。与载体对照相比，联合治疗显着提高了 RCI 后小鼠 30 天的存活率，从 15%（载体治疗）提高到 42%，并将中位生存时间延长了 4 天。此外，与用媒介物治疗的动物相比，联合疗法显着增加了 RCI 小鼠的体重以及骨髓干细胞和祖细胞克隆性，并加速了 RCI 诱导的肠道损伤的恢复。单独使用 L-瓜氨酸治疗也能加速 RCI 后皮肤伤口的愈合。总之，这些数据表明 PEG-G-CSF 和 L-瓜氨酸联合疗法是减轻 RCI 的潜在有效对策，可能是通过提高造血干/祖细胞的存活率并加速 RCI 引起的肠道损伤和皮肤伤口的恢复。
Radiation combined injury (RCI, radiation exposure coupled with other forms of injury, such as burn, wound, hemorrhage, blast, trauma and/or sepsis) comprises approximately 65% of injuries from a nuclear explosion, and greatly increases the risk of morbidity and mortality when compared to that of radiation injury alone. To date, no U.S. Food and Drug Administration (FDA)-approved countermeasures are available for RCI. Currently, three leukocyte growth factors (Neupogen®, Neulasta® and Leukine®) have been approved by the FDA for mitigating the hematopoietic acute radiation syndrome. However these granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) products have failed to increase 30-day survival of mice after RCI, suggesting a more complicated biological mechanism is in play for RCI than for radiation injury. In the current study, the mitigative efficacy of combination therapy using pegylated (PEG)-G-CSF (Neulasta) and L-citrulline was evaluated in an RCI mouse model. L-citrulline is a neutral alpha-amino acid shown to improve vascular endothelial function in cardiovascular diseases. Three doses of PEG-G-CSF at 1 mg/kg, subcutaneously administered on days 1, 8 and 15 postirradiation, were supplemented with oral L-citrulline (1 g/kg), once daily from day 1 to day 21 postirradiation. The combination treatment significantly improved the 30-day survival of mice after RCI from 15% (vehicle-treated) to 42%, and extended the median survival time by 4 days, as compared to vehicle controls. In addition, the combination therapy significantly increased body weight and bone marrow stem and progenitor cell clonogenicity in RCI mice, and accelerated recovery from RCI-induced intestinal injury, compared to animals treated with vehicle. Treatment with L-citrulline alone also accelerated skin wound healing after RCI. In conclusion, these data indicate that the PEG-G-CSF and L-citrulline combination therapy is a potentially effective countermeasure for mitigating RCI, likely by enhancing survival of the hematopoietic stem/progenitor cells and accelerating recovery from the RCI-induced intestinal injury and skin wounds.