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

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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)171-181
Number of pages11
JournalCritical Care Medicine
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 2013

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Thioredoxins
Acute Lung Injury
Orthomyxoviridae
Oxidation-Reduction
Proteins
Chemokine CXCL1
Lung
Lymphotoxin-beta
Bronchoalveolar Lavage
Virus Diseases
Survival Rate
Therapeutics
Neutrophil Infiltration
Influenza A virus
Survival Analysis
Inbred C57BL Mouse
Human Influenza
Pneumonia
Oxidative Stress
Anti-Inflammatory Agents

Keywords

  • acute lung injury
  • cytokine
  • influenza virus
  • mouse
  • oxidative stress
  • thioredoxin-1

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Redox-active protein Thioredoxin-1 administration ameliorates influenza a virus (H1N1)-induced acute lung injury in mice. / 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.

In: Critical Care Medicine, Vol. 41, No. 1, 01.2013, p. 171-181.

Research output: Contribution to journalArticle

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. / Redox-active protein Thioredoxin-1 administration ameliorates influenza a virus (H1N1)-induced acute lung injury in mice. In: Critical Care Medicine. 2013 ; Vol. 41, No. 1. pp. 171-181.
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AU - Matsukawa, Akihiro

AU - Yamada, Mutsuko

AU - Fujii, Yosuke

AU - Nagaoka, Yoshiharu

AU - Tsuge, Mitsuru

AU - Yamashita, Nobuko

AU - Ito, Toshihiro

AU - Yamada, Masao

AU - Masutani, Hiroshi

AU - Yodoi, Junji

AU - Morishima, Tsuneo

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N2 - 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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KW - acute lung injury

KW - cytokine

KW - influenza virus

KW - mouse

KW - oxidative stress

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