title: Redox-active protein thioredoxin-1 administration ameliorates influenza A virus (H1N1)-induced acute lung injury in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Prospective animal trial.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Nine-week-old male C57BL/6 mice inoculated with H1N1.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yashiro
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsukahara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Yamada
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujii
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Nagaoka
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Tsuge
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yamashita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Masao
authors.initials: M
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masutani
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Morishima
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D054360:Chemokine CXCL1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D011024:Pneumonia, Viral / Q000188:drug therapy*; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D013879:Thioredoxins / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects
chemical_list: D000975:Antioxidants; D054360:Chemokine CXCL1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013879:Thioredoxins