Redox-Active Protein Thioredoxin-1 Administration Ameliorates Influenza A Virus (H1N1)-Induced Acute Lung Injury in Mice
Redox-Active Protein Thioredoxin-1 Administration Ameliorates Influenza A Virus (H1N1)-Induced Acute Lung Injury in Mice
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DOI：
10.1097/ccm.0b013e3182676352
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发表时间：
2013-01-01
影响因子：
8.8
通讯作者：
Morishima, Tsuneo
中科院分区：
文献类型：
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作者：
Yashiro, Masato;Tsukahara, Hirokazu;Morishima, Tsuneo
目的：流感病毒感染可引起严重的急性肺损伤，导致显著的发病率和死亡率。硫氧还蛋白-1（Thioredoxin-1，Thioredoxin-1）是一种在应激条件下诱导产生的具有氧化还原活性的防御蛋白。动物实验表明，硫氧还蛋白-1对各种严重疾病具有保护作用。本研究旨在评价重组人硫氧还蛋白-1给药对甲型流感病毒（H1N1）诱导的小鼠急性肺损伤的保护作用。设计：前瞻性动物试验。设置：研究实验室。受试者：接种H1N1的9周龄雄性C57 BL/6小鼠。干预：将小鼠分为赋形剂治疗组和重组人硫氧还蛋白-1治疗组。对于存活率分析，从第-1天至第13天每隔一天腹膜内施用媒介物或重组人硫氧还蛋白-1。对于肺灌洗和病理学分析，在第1、1和3天腹膜内施用载体或重组人硫氧还蛋白-1。测量和主要结果：在接种后24、72和120小时进行肺灌洗和病理学分析。重组人硫氧还蛋白-1治疗显著提高了H1N1接种小鼠的存活率，尽管该治疗不影响病毒在肺中的繁殖。该治疗显着减轻了H1N1接种小鼠肺部的组织学变化和中性粒细胞浸润。该治疗显著减弱了在H1N1接种小鼠中观察到的肺中肿瘤坏死因子-a和趋化因子（C-X-C基序）配体1的产生以及氧化应激增强。H1N1诱导小鼠肺上皮细胞MLE-12表达肿瘤坏死因子-a和趋化因子（C-X-C基序）配体1，而加入重组人硫氧还蛋白-1可抑制这两种因子的表达。重组人硫氧还蛋白-1治疗开始后30分钟H1N1接种也显着提高了小鼠的生存率。结论：外源性给予重组人硫氧还蛋白-1显着提高了小鼠流感肺炎模型的存活率和衰减肺组织学变化。硫氧还蛋白-1的保护机制可能与其有效的抗氧化和抗炎作用有关。因此，重组人硫氧还蛋白-1可能是治疗人类严重流感病毒感染的一种可能的药理学策略。(Crit Care Med 2013; 41：171-181）
Objectives: Influenza virus infections can cause severe acute lung injury leading to significant morbidity and mortality. Thioredoxin-1 is a redox-active defensive protein induced in response to stress conditions. Animal experiments have revealed that thioredoxin-1 has protective effects against various severe disorders. This study was undertaken to evaluate the protective effects of recombinant human thioredoxin-1 administration on influenza A virus (H1N1)-induced acute lung injury in mice.Design: Prospective animal trial.Setting: Research laboratory.Subjects: Nine-week-old male C57BL/6 mice inoculated with H1N1.Intervention: The mice were divided into a vehicle-treated group and recombinant human thioredoxin-1-treated group. For survival rate analysis, the vehicle or recombinant human thioredoxin-1 was administered intraperitoneally every second day from day -1 to day 13. For lung lavage and pathological analyses, vehicle or recombinant human thioredoxin-1 was administered intraperitoneally on days 1, 1, and 3.Measurements and Main Results: Lung lavage and pathological analyses were performed at 24, 72, and 120 hrs after inoculation. The recombinant human thioredoxin-1 treatment significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice. The treatment significantly attenuated the production of tumor necrosis factor-a and chemokine (C-X-C motif) ligand 1 in the lung and oxidative stress enhancement, which were observed in H1N1-inoculated mice. H1N1 induced expressions of tumor necrosis factor-a and chemokine (C-X-C motif) ligand 1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of recombinant human thioredoxin-1. The recombinant human thioredoxin-1 treatment started 30 mins after H1N1 inoculation also significantly improved the survival of the mice.Conclusions: Exogenous administration of recombinant human thioredoxin-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of thioredoxin-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, recombinant human thioredoxin-1 might be a possible pharmacological strategy for severe influenza virus infection in humans. (Crit Care Med 2013; 41:171-181)