Abstract | 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-α 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-α 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.
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Authors | Masato Yashiro, Hirokazu Tsukahara, Akihiro Matsukawa, Mutsuko Yamada, Yosuke Fujii, Yoshiharu Nagaoka, Mitsuru Tsuge, Nobuko Yamashita, Toshihiro Ito, Masao Yamada, Hiroshi Masutani, Junji Yodoi, Tsuneo Morishima |
Journal | Critical care medicine
(Crit Care Med)
Vol. 41
Issue 1
Pg. 171-81
(Jan 2013)
ISSN: 1530-0293 [Electronic] United States |
PMID | 23222257
(Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antioxidants
- Chemokine CXCL1
- Recombinant Proteins
- Tumor Necrosis Factor-alpha
- Thioredoxins
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Topics |
- Acute Lung Injury
(drug therapy, immunology, pathology, virology)
- Animals
- Antioxidants
(pharmacology, therapeutic use)
- Chemokine CXCL1
(drug effects, metabolism)
- Humans
- Influenza A Virus, H1N1 Subtype
- Influenza, Human
(drug therapy)
- Male
- Mice
- Mice, Inbred C57BL
- Neutrophil Infiltration
(drug effects)
- Pneumonia, Viral
(drug therapy)
- Prospective Studies
- Recombinant Proteins
(pharmacology, therapeutic use)
- Survival Analysis
- Thioredoxins
(pharmacology, therapeutic use)
- Tumor Necrosis Factor-alpha
(drug effects, metabolism)
- Viral Load
(drug effects)
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