刘思炜,肖玲,徐海霞,程佳乐,田力,刘忠

• 1:中国医学科学院输血研究所
• 2:中国医学科学院系统研究所

摘要(Abstract)：

目的 探讨铁死亡在输血相关急性肺损伤(transfusion-related acute lung injury, TRALI)中的作用机制，评价特异性抑制剂Ferrostatin-1(Fer-1)疗效，为防治TRALI提供依据。方法 本研究采用“二次打击”模型构建小鼠TRALI,通过生存曲线分析、肺组织湿干重比(W/D)、髓过氧化物酶(MPO)活性、总蛋白浓度等指标判断建模效果。建模成功后首先明确TRALI中是否发生铁死亡，收集TRALI模型组、LPS组及Control组(n=6)标本，通过检测铁死亡关键指标[包括肺组织铁含量、丙二醛(MDA)、脂质过氧化产物(LPO)及相关蛋白(GPX4、ACSL4)表达]进行分析。其次，增设Fer-1组评估其的防治效果，动态监测4组(n=6)小鼠存活率及临床症状，评估肺损伤程度，同时检测铁死亡相关指标以阐明Fer-1的保护作用机制。结果 TRALI建模成功。相较于Control组和LPS组，TRALI组小鼠肺组织二价铁含量[(18.32±1.11)nmol/well]、MDA[(14.68±0.96)μmol/L]及LPO[(1.60±0.02)μmol/L]水平显著升高(均P<0.01),伴随GPX4蛋白下调和ACSL4上调。Fer-1预处理可显著逆转上述异常：W/D降至4.01±0.43,MPO活性显著下降[Fer-1组(21 606±4 235)pg/mL vs TRALI组(30 724±2 616)pg/mL],Fer-1组肺组织总蛋白浓度较TRALI组下降了约40.8%(均P<0.01),以上指标变化均说明用药后小鼠肺损伤程度减轻。Fer-1干预后二价铁含量[(7.46±1.83)nmol/well]恢复至接近Control组[(5.48±0.70)nmol/well]水平，脂质过氧化水平检测进一步发现，Fer-1干预使MDA和LPO含量分别下降35.8%、29.4%(P<0.001),且GPX4、ACSL4蛋白表达水平恢复至近正常小鼠水平(均P>0.05)。结论 TRALI的进展与铁死亡激活密切相关，其特征为铁超载、脂质过氧化积累及GPX4/ACSL4失衡；Ferrostatin-1通过抑制铁死亡通路显著减轻肺水肿与炎症损伤，提示靶向抑制铁死亡可能为TRALI提供新的治疗策略。

关键词(KeyWords)： 铁死亡;输血相关急性肺损伤;Ferrostatin-1;脂质过氧化;二次打击模型

Abstract:

Keywords:

基金项目(Foundation): 血液安全预警体系构建及干预研究(2024)(2021-I2M-1-060-2024-C0)

作者(Author): 刘思炜,肖玲,徐海霞,程佳乐,田力,刘忠

DOI: 10.13303/j.cjbt.issn.1004-549x.2025.08.002

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