Redox-active protein thioredoxin-1 administration ameliorates influenza A virus (H1N1)-induced acute lung injury in mice

• Published in: Critical care medicine Vol. 41; no. 1; p. 171
• Main Authors: Yashiro, Masato, Tsukahara, Hirokazu, Matsukawa, Akihiro, Yamada, Mutsuko, Fujii, Yosuke, Nagaoka, Yoshiharu, Tsuge, Mitsuru, Yamashita, Nobuko, Ito, Toshihiro, Yamada, Masao, Masutani, Hiroshi, Yodoi, Junji, Morishima, Tsuneo
• Format: Journal Article
• Language: English
• Published: United States 01.01.2013
• Subjects: Acute Lung Injury - drug therapy; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Acute Lung Injury - virology; Animals; Antioxidants - pharmacology; Antioxidants - therapeutic use; Chemokine CXCL1 - drug effects; Chemokine CXCL1 - 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; Recombinant Proteins - therapeutic use; Survival Analysis; Thioredoxins - pharmacology; Thioredoxins - therapeutic use; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism; Viral Load - drug effects
• ISSN: 1530-0293
• DOI: 10.1097/ccm.0b013e3182676352

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. Prospective animal trial. Research laboratory. Nine-week-old male C57BL/6 mice inoculated with H1N1. 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. 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. 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.