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 (rhTRX-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 vehicle-treated group and rhTRX-1-treated group. For survival rate analysis, the vehicle or rhTRX-1 was administered intraperitoneally every second day from Day -1 to Day 13. For lung lavage and pathological analyses, vehicle or rhTRX-1 was administered intraperitoneally on Day -1, 1, and 3.
Measurements and Main Results:Lung lavage and pathological analyses were performed at 24, 72, and 120 hr after inoculation. The rhTRX-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 TNF-α and CXCL1 in the lung and oxidative stress enhancement which were observed in H1N1-inoculated mice. H1N1 induced expressions of TNF-α and CXCL1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of rhTRX-1. The rhTRX-1 treatment started 30 min after H1N1 inoculation also significantly improved the survival of the mice.
Conclusions:Exogenous administration of rhTRX-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of TRX-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, rhTRX-1 might be a possible pharmacological strategy for severe influenza virus infection in humans.
3Influenza virus infections cause a broad array of illnesses that are responsible for significant morbidity and mortality both in children and adults on a yearly basis (1). Influenza can cause periodic global pandemics with even higher penetrance of illness. Highly pathogenic avian influenza virus H5N1 emerged in 1996 in Hong Kong, China (2). Although cases of avian influenza infections have decreased since 2006, the emergence of a pandemic strain remains a threat. In 2009, novel swine-origin influenza virus H1N1 was identified in Mexico. It continues to spread globally (3).Several antiviral compounds have been developed against influenza virus to interfere with specific events in the replication cycle. Under treatment with these drugs, however, influenza virus infection occasionally causes severe pneumonia, necessitating intensive care and mechanical ventilat...