Ultra-High-Dose-Rate FLASH Irradiation Limits Reactive Gliosis in the Brain.
Ultra-High-Dose-Rate FLASH Irradiation Limits Reactive Gliosis in the Brain.
复制标题
超高剂量速率闪光照射限制大脑中的反应性神经胶质病。
DOI：
10.1667/rade-20-00067.1
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发表时间：
2020-12-01
影响因子：
3.4
通讯作者：
Acharya MM
中科院分区：
文献类型：
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作者：
Montay-Gruel P;Markarian M;Allen BD;Baddour JD;Giedzinski E;Jorge PG;Petit B;Bailat C;Vozenin MC;Limoli C;Acharya MM
以常规剂量率（CONV，0.1-2.0 Gy/min）进行的脑放射治疗会引起各种暂时不同的损伤特征，这些损伤特征总是涉及持续的神经炎症迹象。过去的研究表明，先天免疫系统和适应性免疫系统都参与调节中枢神经系统（CNS）辐射损伤反应，其中星形胶质细胞增生、小胶质细胞增生和细胞因子信号传导的升高定义了正常组织毒性的复杂模式，这种模式永远不会完全解决。这些副作用构成成人和儿童患者中枢神经系统恶性肿瘤治疗的主要限制。据报道，一种称为 FLASH 放射治疗（FLASH-RT，瞬时剂量率 ≥ 106 Gy/s；10 Gy 在 1.8 μs 的 1-10 个脉冲中传递）的新型超高剂量率照射方式的出现，可最大限度地减少通常与 CONV 暴露同时发生的一系列正常组织毒性，这种效应被称为“FLASH 效应”。由于现已发现FLASH效应可显着限制大脑中持续的炎症特征，因此我们试图进一步阐明星形胶质细胞增生的变化是否可以解释受辐射大脑的不同剂量率反应。在这里，我们报告说，与 CONV 照射的动物相比，FLASH 照射后为激活星形胶质细胞增生和大脑中免疫信号传导选择的标记物（胶质纤维酸性蛋白，GFAP；Toll 样受体 4，TLR4）的表达水平降低。有趣的是，虽然 FLASH-RT 不会诱导星形胶质细胞增生和 TLR4，但与对照组相比，补体 C1q 和 C3 的表达水平在 FLASH 和 CONV 照射方式中均被发现升高。尽管中枢神经系统的功能结果仍有待根据报告的蛋白质表达的具体变化进行交叉验证，但这些数据提供了令人信服的证据，可以区分受辐射大脑中正常组织损伤的剂量率反应。
Encephalic radiation therapy delivered at a conventional dose rate (CONV, 0.1–2.0 Gy/min) elicits a variety of temporally distinct damage signatures that invariably involve persistent indications of neuroinflammation. Past work has shown an involvement of both the innate and adaptive immune systems in modulating the central nervous system (CNS) radiation injury response, where elevations in astrogliosis, microgliosis and cytokine signaling define a complex pattern of normal tissue toxicities that never completely resolve. These side effects constitute a major limitation in the management of CNS malignancies in both adult and pediatric patients. The advent of a novel ultra-high dose-rate irradiation modality termed FLASH radiotherapy (FLASH-RT, instantaneous dose rates ≥ 106 Gy/s; 10 Gy delivered in 1–10 pulses of 1.8 μs) has been reported to minimize a range of normal tissue toxicities typically concurrent with CONV exposures, an effect that has been coined the “FLASH effect.” Since the FLASH effect has now been found to significantly limit persistent inflammatory signatures in the brain, we sought to further elucidate whether changes in astrogliosis might account for the differential dose-rate response of the irradiated brain. Here we report that markers selected for activated astrogliosis and immune signaling in the brain (glial fibrillary acidic protein, GFAP; toll-like receptor 4, TLR4) are expressed at reduced levels after FLASH irradiation compared to CONV-irradiated animals. Interestingly, while FLASH-RT did not induce astrogliosis and TLR4, the expression level of complement C1q and C3 were found to be elevated in both FLASH and CONV irradiation modalities compared to the control. Although functional outcomes in the CNS remain to be cross-validated in response to the specific changes in protein expression reported, the data provide compelling evidence that distinguishes the dose-rate response of normal tissue injury in the irradiated brain.