Thrombin Impairs Alveolar Fluid Clearance by Promoting Endocytosis of Na+,K+-ATPase

István Vadász, Rory E. Morty, Andrea Olschewski, Melanie Königshoff, Markus G. Kohstall, Hossein A. Ghofrani, Friedrich Grimminger, Werner Seeger
2005 American Journal of Respiratory Cell and Molecular Biology  
Coagulation is an emerging area of interest in the pathogenesis and treatment of acute lung injury. Concentrations of the edemagenic coagulation protease thrombin are elevated in plasma and lavage fluids from afflicted patients. We explored the impact of thrombin on the formation and resolution of alveolar edema. Intravascularly applied thrombin inhibited active transepithelial 22 Na transport in intact rabbit lungs, suppressing alveolar fluid clearance. Epithelial permeability was unaffected,
more » ... hereas endothelial permeability was increased. In A549 human lung epithelial cells and in mouse primary alveolar type II cells, thrombin blocked ouabain-sensitive Na ϩ ,K ϩ -ATPase-mediated 86 Rb ϩ uptake, without altering amiloride-sensitive sodium currents. Furthermore, thrombin downregulated cell-surface expression of Na ϩ ,K ϩ -ATPase, but not ENaC ␣ and ␤ subunits. The endocytosis inhibitor phalloidin oleate blocked all thrombin-induced effects on sodium transport activity. Similarly, diphenyleneiodonium chloride, an inhibitor of reactive oxygen radical production, as well as a protein kinase C-inhibitor, prevented these thrombin-induced effects. Thus, thrombin signaling via reactive oxygen species and protein kinase C-promotes Na ϩ ,K ϩ -ATPase endocytosis, resulting in loss of function. We propose here a dual role for thrombin in mediating disturbances to fluid balance in the lung: thrombin concomitantly provokes edema formation by increasing endothelial permeability, and inhibits alveolar edema resolution by blocking Na ϩ ,K ϩ -ATPase function.
doi:10.1165/rcmb.2004-0407oc pmid:16014898 fatcat:7r4adlzjxfdcpkstqgxfivvxsu