Acute lung injury (ALI) and its more severe form acute respiratory distress (ARD) can result from infectious agents, including several strains of influenza A virus. Recent evidence suggests that excessive production of reactive oxygen species (ROS) is a major contributor to ALI caused by influenza. We evaluated the effects of TG6-44, a novel inhibitor of ROS production, in in vitro and in vivo models of influenza A virus infection. In vitro, using the monocytic cells (THP-1) and human PBMC infected with influenza A virus (X31), we found that TG6-44 treatment decreased virus-induced ROS and inflammatory markers in THP1 (IL6, IFNγ , MCP1, TNFα , MIP1β) and in PBMC (IL6, IL8, TNFα , MCP1). Also, in influenza A virus-infected THP1 cells, TG6-44 treatment led to a reduction in virus-induced cell death as evidenced by decreased Caspase3 activation, decreased proportion of Annexin V+/PI+ cells, and increased Bcl2 phosphorylation. Notably, TG6-44-treatment decreased the proportion of THP1 cells expressing viral nucleoprotein and delayed its translocation into the nucleus. Moreover, mice infected with a lethal dose of influenza A virus (PR8) and given TG6-44 had both reduced levels of virus-induced inflammatory markers in lungs and a higher survival rate compared to controls. Taken together, our results demonstrate anti-inflammatory and anti-infective effects of TG6-44, and suggest ROS-inhibitors as valuable adjunct therapeutics to reduce ALI/ARD caused by influenza A virus infection.
- Copyright © 2013 by The American Association of Immunologists, Inc.