Journal article

Publication year: 2016

Pages: 1566-1580

Journal: The Journal of Clinical Investigation

Volume number: 126

Issue number: 4

ISSN: 0021-9738

eISSN: 1558-8238

Open access status: Green

DOI Link: https://doi.org/10.1172/JCI83931

Publisher: American Society for Clinical Investigation

Abstract: 
Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis-inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury.

Harvard Citation style: Peteranderl, C., Morales-Nebreda, L., Selvakumar, B., Lecuona, E., Vadasz, I., Morty, R., et al. (2016) Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection, The Journal of Clinical Investigation, 126(4), pp. 1566-1580. https://doi.org/10.1172/JCI83931

APA Citation style: Peteranderl, C., Morales-Nebreda, L., Selvakumar, B., Lecuona, E., Vadasz, I., Morty, R., Schmoldt, C., Bespalowa, J., Wolff, T., Pleschka, S., Mayer, K., Gattenloehner, S., Fink, L., Lohmeyer, J., Seeger, W., Sznajder, J., Mutlu, G., Budinger, G., & Herold, S. (2016). Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. The Journal of Clinical Investigation. 126(4), 1566-1580. https://doi.org/10.1172/JCI83931