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Published ahead of print on July 13, 2005, doi:10.1165/rcmb.2004-0407OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 4, October 2005, 343-354

A more recent version of this article appeared on October 1, 2005
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Submitted on December 20, 2004
Revised on July 12, 2005

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

Istvan Vadasz1, Rory E Morty1, Andrea Olschewski1, Melanie Konigshoff1, Markus G Kohstall1, Hossein A Ghofrani1, Friedrich Grimminger1, and Werner Seeger1*

1 University of Giessen Lung Center, Justus Liebig-University, Giessen, Germany

* To whom correspondence should be addressed. E-mail: Werner.Seeger{at}innere.med.uni-giessen.de.

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 22Na transport in intact rabbit lungs, suppressing alveolar fluid clearance. Epithelial permeability was unaffected, while endothelial permeability was increased. In A549 human lung epithelial cells and in mouse primary alveolar type II cells, thrombin blocked ouabain-sensitive Na+,K+-ATPase-mediated 86Rb+ uptake, without altering amiloride-sensitive sodium currents. Furthermore, thrombin down-regulated cell-surface expression of Na+,K+-ATPase, but not ENaC {alpha} and {beta} 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-{zeta} inhibitor, prevented these thrombin-induced effects. Thus, thrombin signaling via reactive oxygen species and protein kinase C-{zeta} promotes Na+,K+-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+,K+-ATPase function.




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