FLASH irradiation-induced acute lung injury promotes metastatic colonization via neutrophil extracellular trap formation

IF 3.2 2区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Medical physics Pub Date : 2025-09-30 DOI:10.1002/mp.70054

Hui Luo, Chengliang Yang, Marie-Catherine Vozenin, Ronghu Mao, Leijie Ma, Hongchang Lei, Hong Ge

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Abstract

Background

FLASH irradiation, a technique that delivers prescribed dose at ultra-high dose rate, has been described to alleviate normal tissue injury in multiple animal models. However, the underlying mechanism was not fully understood.

Purpose

We aimed to investigate whether FLASH irradiation-induced acute lung injury could reduce metastatic colonization compared with conventional (CONV) irradiation.

Methods

Healthy lungs of C57BL/6J male mice were irradiated with either FLASH or CONV, SV2 lung adenocarcinoma cells were intravenously injected and healthy lung volume was monitored using micro-computed tomography (micro-CT). The irradiated tissues (tumor + normal parenchyma) were analyzed by proteomic to identify key regulators of cancer progression. Key proteins were preliminarily validated using real-time quantitative PCR and western blot. Further validation was carried out by inhibiting or promoting neutrophil extracellular traps (NETs) formation within in vivo models.

Results

In radiation-induced acute lung injury models, both CONV and FLASH involved in equivalent and enhanced metastatic colonization. Follow-up molecular analysis using proteomic profiling revealed NETs formation involved in cancer progression. Both radiation modalities triggered acute lung injury and inflammatory response with a similar pattern. Inhibiting NETs formation significantly delay tumor metastasis in either FLASH or CONV, whereas stimulating NETs formation markedly accelerate cancer progression.

Conclusion

These experiments suggest that healthy lung spare does not recapitulate at acute time point after exposure to FLASH. Proteomic analyses suggest a possible role for NETs formation within the tumor microenvironment in deriving cancer cell seeding. NETs formation could be served as a prognostic factor in thoracic cancer.

Abstract Image

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闪光照射诱导的急性肺损伤通过中性粒细胞胞外陷阱的形成促进转移定植。

背景：FLASH照射是一种以超高剂量率提供规定剂量的技术，已被描述为减轻多种动物模型的正常组织损伤。然而，其潜在机制尚未完全了解。目的：我们旨在研究与常规（CONV）照射相比，FLASH照射诱导的急性肺损伤是否能减少转移性定植。方法：用FLASH或CONV照射C57BL/6J雄性小鼠健康肺，静脉注射SV2肺腺癌细胞，用微计算机断层扫描（micro-CT）监测健康肺体积。通过蛋白质组学分析辐照组织（肿瘤+正常实质）以确定癌症进展的关键调节因子。采用实时定量PCR和western blot对关键蛋白进行初步验证。通过在体内模型中抑制或促进中性粒细胞胞外陷阱（NETs）的形成，进一步验证了这一点。结果：在辐射诱导的急性肺损伤模型中，CONV和FLASH都参与了等效的和增强的转移性定植。使用蛋白质组学分析的后续分子分析显示，NETs的形成参与了癌症的进展。两种放射方式引发的急性肺损伤和炎症反应具有相似的模式。抑制NETs形成可显著延缓FLASH或CONV的肿瘤转移，而刺激NETs形成可显著加速癌症进展。结论：这些实验表明，健康的肺备用在暴露于FLASH后的急性时间点不会重现。蛋白质组学分析表明，肿瘤微环境中NETs的形成可能在衍生癌细胞播种中起作用。NETs的形成可作为胸癌的预后因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Medical physics 医学-核医学

CiteScore

6.80

自引率

15.80%

发文量

660

审稿时长

1.7 months

期刊介绍： Medical Physics publishes original, high impact physics, imaging science, and engineering research that advances patient diagnosis and therapy through contributions in 1) Basic science developments with high potential for clinical translation 2) Clinical applications of cutting edge engineering and physics innovations 3) Broadly applicable and innovative clinical physics developments Medical Physics is a journal of global scope and reach. By publishing in Medical Physics your research will reach an international, multidisciplinary audience including practicing medical physicists as well as physics- and engineering based translational scientists. We work closely with authors of promising articles to improve their quality.