| 罗辉,王刘祥,Ron Leavitt,等.全肺FLASH和常规剂量率照射后小鼠血浆差异蛋白质组学分析[J].中华放射医学与防护杂志,2025,45(10):941-948.Luo Hui,Wang Liuxiang,Ron Leavitt,et al.Proteomic analysis of differentially expressed proteins in mice plasma following FLASH and conventional dose rate whole-lung irradiation[J].Chin J Radiol Med Prot,2025,45(10):941-948 |
| 全肺FLASH和常规剂量率照射后小鼠血浆差异蛋白质组学分析 |
| Proteomic analysis of differentially expressed proteins in mice plasma following FLASH and conventional dose rate whole-lung irradiation |
| 投稿时间：2024-09-23 |
| DOI：10.3760/cma.j.cn112271-20240923-00373 |
| 中文关键词: FLASH照射 肿瘤控制 急性放射性肺损伤 蛋白质组学 |
| 英文关键词:FLASH irradiation Tumor control Acute radiation-induced lung injury Proteomics |
| 基金项目:河南省科技攻关计划(212102310619) |
| 作者 | 单位 | E-mail | | 罗辉 | 郑州大学附属肿瘤医院放疗科, 郑州 450008 | | | 王刘祥 | 郑州大学医学科学院, 郑州 450001 | | | Ron Leavitt | 洛桑大学附属医院放疗科, 洛桑 瑞士 1002 | | | Jackie Romero | 洛桑大学附属医院放疗科, 洛桑 瑞士 1002 | | | Marie-Catherine Vozenin | 洛桑大学附属医院放疗科, 洛桑 瑞士 1002 | | | Aymeric Almeida | 洛桑大学附属医院放疗科, 洛桑 瑞士 1002 | | | 杨成梁 | 郑州大学附属肿瘤医院放疗科, 郑州 450008 | | | 李娜 | 山东第一医科大学 山东省医学科学院放射学院, 泰安 271021 | | | 王雪楠 | 山东第一医科大学 山东省医学科学院放射学院, 泰安 271021 | | | 毛荣虎 | 郑州大学附属肿瘤医院放疗科, 郑州 450008 | | | 马蕾杰 | 郑州大学附属肿瘤医院放疗科, 郑州 450008 | | | 雷宏昌 | 郑州大学附属肿瘤医院放疗科, 郑州 450008 | | | 葛红 | 郑州大学附属肿瘤医院放疗科, 郑州 450008 | zlyygehong0199@zzu.edu.cn |
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| 中文摘要: |
| 目的 观察电子线FLASH和常规剂量率照射(简称常规照射)的肿瘤控制情况及放射性肺损伤程度，通过蛋白组学方法比较小鼠全肺FLASH照射和常规照射后血浆蛋白质表达谱的变化。方法 采用随机数表法将小鼠随机分为3组：转移癌组、常规照射组、FLASH照射组、每组6只。构建小鼠肺转移癌模型，实施全肺照射，监测正常肺容量的变化。构建小鼠放射性肺损伤模型，观察全肺常规剂量率和FLASH照射后肺组织病理改变。收集接受全肺常规和FLASH照射小鼠血浆标本各5例，与健康对照组比较。采用同位素标记相对和绝对定量(iTRAQ)蛋白质组学技术分析血浆样品，通过高通量生物信息学分析筛选并鉴定差异蛋白质。进一步使用STRING数据库和Cytoscape软件进行蛋白质相互作用网络(PPI)分析，以筛选出关键基因。结果 与转移癌组相比，全肺FLASH和常规剂量率照射肿瘤控制情况相一致。FLASH较常规照射显著减轻肺损伤。血浆蛋白组学分析共鉴定到609个蛋白。其中，FLASH照射组与常规照射组相比，筛选到89个差异蛋白。基因本体论(GO)分析显示，上调表达基因主要涉及应激反应和炎症应答，而对三磷酸腺苷(ATP)代谢和血管生成调控的基因下调表达。京都基因与基因组百科全书(KEGG)富集分析结果表明，上调表达基因主要富集于未折叠蛋白应答通路，而下调表达基因主要涉及代谢通路和氧化磷酸化等过程。通过PPI分析及反转录-聚合酶链反应(RT-PCR)验证得到4个关键基因。结论 FLASH与常规照射相比，可减轻正常肺组织放射损伤，且保持相同的肺转移癌杀伤效果。通过蛋白质组学分析FLASH和常规照射后血浆中的差异表达蛋白，能够为揭示FLASH效应的分子机制提供线索。 |
| 英文摘要: |
| Objective To observe the tumor control and the degree of radiation-induced lung injury (RILI) between FLASH irradiation and conventional dose rate (CONV) irradiation, and compare the changes in plasma proteomic profiles of mice following whole-lung FLASH and CONV irradiation using proteomics method. Methods A mouse model with metastatic lung cancer was established. After whole-lung irradiation, changes in normal lung capacity were monitored using CT scans. Then, a RILI model was constructed to examine pathological alterations in lung tissues following whole-lung CONV and FLASH irradiation. Plasma samples were collected from mice receiving whole-lung CONV irradiation (n = 5) and whole-lung FLASH irradiation (n = 5), followed by comparison with samples from the control group of healthy mice (also referred to as the healthy control group). These plasma samples were analyzed using isobaric tags for relative and absolute quantification (iTRAQ) -based proteomics, followed by the screening and identification of differentially expressed proteins using high-throughput bioinformatics. Moreover, protein-protein interaction (PPI) network analysis was conducted to identify hub genes using the STRING database and Cytoscape software. Results Whole-lung FLASH and CONV irradiation produced consistent tumor control, with the former significantly reducing RILI compared to the latter. A total of 609 proteins were identified through proteomic analysis. Among them, 89 differentially expressed proteins were detected in the whole-lung FLASH group. Gene Ontology (GO) enrichment analysis indicated that up-regulated genes were primarily associated with stress and inflammatory responses, whereas down-regulated genes were related to ATP metabolism and angiogenesis regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that up-regulated genes were predominantly enriched in unfolded protein response pathways, while down-regulated genes were mainly involved in metabolic pathways and oxidative phosphorylation. Integrated PPI analysis and subsequent validation via reverse transcription-polymerase chain reaction (RT-PCR) revealed four key genes. Conclusions Compared to the whole-lung CONV irradiation, whole-lung FLASH irradiation reduces the RILI of normal lung tissues while maintaining equivalent tumor control in metastatic lung cancer. Proteomic analysis of differentially expressed proteins in plasma after whole-lung FLASH and CONV irradiation provides valuable insights into the molecular mechanisms underlying the FLASH effect. |
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