RT Journal Article
SR Electronic
T1 Late-breaking abstract: Influenza A virus infection reduces alveolar fluid clearance by activation of AMPK and subsequent reduction of Na,K-ATPase protein abundance
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P3921
VO 44
IS Suppl 58
A1 Christin Becker
A1 Emilia Lecuona
A1 Thorsten Wolff
A1 Istvan Vadasz
A1 Rory Morty
A1 Jürgen Lohmeyer
A1 Werner Seeger
A1 Iasha Sznajder
A1 Gokhan Mutlu
A1 Scott Budinger
A1 Susanne Herold
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P3921.abstract
AB Influenza A virus (IV) infection can cause primary viral pneumonia resulting in acute respiratory distress syndrome (ARDS) associated with edema formation. As the capability to clear excessive water from the alveolar compartment is of particular importance for the patients' survival, we aimed to elucidate mechanism that diminish alveolar fluid clearance (AFC) after IV-infection.The regulation of Na,K-ATPase after IV-infection was determined in primary human or murine alveolar epithelial cells (AEC) in monoculture or coculture with murine alveolar macrophages and in mouse lung homogenates (LH) by Western blot or flow cytometric analysis. AFC was measured 8 hours post infection in vitro or 2 days post infection in vivo.We found significantly reduced rates of AFC in IV-infected mice as well as a reduction of Na,K-ATPase-dependant fluid clearance after IV-infection in vitro. Na,K-ATPase alpha1 subunit protein levels were significantly reduced in AEC and LH after IV-infection, partly induced by presence of infected macrophages or accordingly by addition of recombinant TRAIL or IP10. Furthermore we could show that the downregulation of Na,K-ATPase was mediated by Ca2+ signalling and subsequent activation of CaMKKbeta and AMPK. Interfering with this pathway in vivo by adenoviral delivery and overexpression of a dominant-negative form of AMPK could restore AFC after IV-infection.We provide evidence that AFC in IV-infection is impaired by affecting Na,K-ATPase expression levels and that targeting the underlying signalling pathway might provide targets for new treatments increasing edema clearance in IV-induced ARDS.αα