PURPOSE One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. "FLASH" irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity. EXPERIMENTAL DESIGN Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc-/- mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro. RESULTS In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc-/- mice harboring critically short telomeres and lack of telomerase activity. CONCLUSIONS The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.

中文翻译：

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闪光灯辐射可节省肺祖细胞并限制放射性衰老的发生。

目的抗癌放射疗法的主要限制之一在于对位于放射野内的健康组织的不可逆损害。在非常高的剂量率下进行“ FLASH”照射是一种新的治疗方式，据报道可以在动物模型中特异性地使正常组织免于后期辐射诱发的毒性，因此可能是降低治疗毒性的一种有前途的策略。实验设计在急性伤口愈合阶段以及后期使用C57BL / 6J野生型和Terc-暴露于双侧胸腔照射的小鼠以及体外生长的人肺细胞。结果体外研究提供了利用FLASH降低DNA损伤水平并诱导致死性的证据。在小鼠肺中，sc-RNA-seq和对增殖细胞的监测表明，FLASH可以最大限度地减少促炎基因的诱导，并减少损伤后祖细胞的增殖。在后期，经FLASH照射的肺部比CONV暴露后的持久性DNA损伤和衰老细胞少，这表明用FLASH进行肺部再生的可能性更高。与此假设相一致，在具有严重短端粒且缺乏端粒酶活性的Terc-/-小鼠中，FLASH的有益作用丧失了。结论该结果表明，与常规放疗相比，FLASH可使正常细胞中的DNA损伤最小化，使肺祖细胞免于过度损伤，