The role of matrix metalloproteinases (MMP) and their inhibitor in influenza A virus-induced host lung injury

Abstract

Acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) is a major cause of death during influenza pneumonia. Our recent studies provide evidence for the involvement of recruited neutrophils, their toxic enzymes, such as myeloperoxidase and matrix metalloprotenases (MMPs) and neutrophil extracellular traps (NETs) in aggravating alveolar-capillary damage. In the present study, we investigated the effects of Doxycycline (DOX) treatment, an inhibitor of MMPs, on influenza-induced ALI. BALB/c female mice were infected with mouse-adapted influenza A/Aichi/2/68 (H3N2) virus and administered daily with 20 mg/kg or 60 mg/kg doxycycline orally. The effects of DOX on ALI were determined by measuring inflammation, capillary leakage and MMP-9 activities. Furthermore, levels of T1-a (membrane protein of alveolar type I epithelium) and thrombomodulin (endothelial protein) were evaluated by western blot analysis in the bronchoalveolar lavage fluid (BALF). Our results demonstrate significant reduction of inflammation and protein leakage in the lungs after DOX treatment. MMP-9 activity and levels of T1-a and thrombomodulin were also decreased in DOX-treated group. These results were corroborated with histopathology analysis, which demonstrated significant decrease in lung damage. Although DOX reduced ALI, there were no effects on virus titers and body weights. Taken together these results demonstrate that DOX can be a promising drug in alleviating ALI during influenza pneumonia. Further studies need to be tested to determine whether DOX can be used as a combination drug together with anti-viral agents to contain severe influenza pneumonia.