环丙沙星和聚乙二醇化 G-CSF 联合治疗减轻了电离辐射引起的脑出血和死亡率。
Ciprofloxacin and pegylated G-CSF combined therapy mitigates brain hemorrhage and mortality induced by ionizing irradiation.
机构信息
Radiation Combined Injury Program, Department of Scientific Research, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States.
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
出版信息
Front Public Health. 2023 Dec 14;11:1268325. doi: 10.3389/fpubh.2023.1268325. eCollection 2023.
INTRODUCTION
Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP.
METHODS
B6D2F1 female mice were exposed to Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3).
RESULTS
CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased.
DISCUSSION
CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.
简介
脑出血发生在急性全身 9.5GyCo-γ 照射后 13 至 16 天。本研究测试了减轻脑出血和提高辐射后存活率的对策。此前，我们发现聚乙二醇化 G-CSF 治疗（PEG）（即 FDA 批准的药物 Neulasta）可将辐射后的存活率提高 20-40%。本研究探讨了环丙沙星（CIP）是否可以增强 PEG 诱导的存活率，以及 PEG 单独或与 CIP 联合是否可以减轻辐射引起的脑出血。
方法
B6D2F1 雌性小鼠接受 Co-γ 辐射。用 CIP 喂养小鼠 21 天。PEG 于第 1、8 和 15 天注射。用载体、CIP、PEG 或 PEG+CIP 处理的小鼠研究 30 天存活率和体重减轻。在辐射后第 2、4、9 和 15 天以及第 15 天收集血液和胸骨以及大脑，以研究血小板数量、脑出血和组织病理学。用胶质纤维酸性蛋白（GFAP）、p53、p16、白细胞介素 18（IL-18）、ICAM1、Claudin2、ZO-1 和补体蛋白 3（C3）检测小脑/脑桥/延髓。
结果
CIP+PEG 使辐射后的存活率提高了 85%，而 PEG 单独使存活率提高了 30%。辐射耗尽了血小板，PEG 或 CIP+PEG 可减轻血小板的减少。观察到脑出血，包括表面和颅内出血，而假手术组小鼠无出血。CIP 或 CIP+PEG 可显著减轻脑出血。IR 降低了 CIP 或 CIP+PEG 恢复的 GFAP 水平，但 PEG 单独不能恢复。IR 仅在第 4 天增加了 IL-18 水平，而 CIP 单独、PEG 单独或 CIP+PEG 可抑制该水平的增加。IR 在第 4 天和第 15 天增加了 C3，这与第 15 天的脑出血发生时间一致。IR 增加了磷酸化 p53 和 p53 水平，CIP、PEG 或 CIP+PEG 可减轻该水平的增加。p16、Claudin2 和 ZO-1 没有改变；ICAM1 增加。
讨论
CIP+PEG 使辐射后的存活率提高了 85%，而 PEG 单独使存活率提高了 30%。IR 后脑出血、C3 增加和 p53 激活同时发生，表明它们参与了 IR 引起的脑损伤。CIP+PEG 可有效减轻脑损伤，提示 CIP+PEG 疗法通过恢复 GFAP 和血小板、降低 C3 和 p53 来治疗 IR 引起的脑出血的有效性。
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