Combination of ribavirin and reduning protects mice against severe pneumonia induced by H1N1 influenza a virus

OBJECTIVE:To investigate the effects of ribavirin administration combined with Reduning in a mouse model of influenza A(H1N1)-induced severe pneumonia.METHODS:Influenza A/Beijing/501/2009(H1N1)-infected C57BL/6 mice were randomly divided into four experimental groups treated with either a mock injection of phosphate-buffered saline(PBS),ribavirin(66.6 mg/kg daily)or Reduning(86.6 mg/kg daily),or a combination of both,for 7 days.Mice were monitored for clinical signs and survival,and body weight was measured daily for 14 days.Virus titer,lung wet-to-dry ratios,pathology and cytokines including interleukin(IL)-6,IL-10,and interferon(IFN)-γwere assayed on different days.RESULTS:In the untreated group injected with phosphate buffer saline,all the mice died of the infection.The survival rate of mice treated with Reduning was only 10%,whereas 100%of the ribavirin-and the combination-treated mice survived.Low lung viral loads indicated that ribavirin significantly inhibited virus replication,whereas Reduning did not.Lung wet-to-dry ratios demonstrated that both ribavirin and Reduning,administered together or separately,reduced acute lung edema compared with results in the untreated group.Pathology analyses also showed that treatment with a combination of both drugs relieved pathological lesions,whereas the single drug treatment did not.Levels of IL-6,IL-10 and IFN-γin mice treated with ribavirin or the combination of both ribavirin and Reduning were all significantly lower than in the untreated group,especially in the combination-treated group.In addition,Reduning administration significantly decreased both IL-6 and IL-10production but had no effect on IFN-γ.CONCLUSION:Due to the synergistic effect of antiviral and antiinflammation,the combination of ribavirin and Reduning could be an effective treatment for severe H1N1 which was considered to be significant to delayed antiviral and drug resistant.