This Article Full Text Full Text (PDF) All Versions of this Article: 2004-0407OCv1 33/4/343    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vadász, I. Articles by Seeger, W. Search for Related Content PubMed PubMed Citation Articles by Vadász, I. Articles by Seeger, W.

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

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

Correspondence and requests for reprints should be addressed to Werner Seeger, M.D., University of Giessen Lung Center, Medical Clinic II, Justus Liebig University, Klinikstrasse 36, D-35392 Giessen, Germany. 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, whereas 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 downregulated cell-surface expression of Na⁺,K⁺-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⁺,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.

Key Words: acute respiratory distress syndrome • coagulation • permeability • protein kinase C- • reactive oxygen species

This article has been cited by other articles:

				M. Konigshoff, A. Wilhelm, A. Jahn, D. Sedding, O. V. Amarie, B. Eul, W. Seeger, L. Fink, A. Gunther, O. Eickelberg, et al. The Angiotensin II Receptor 2 Is Expressed and Mediates Angiotensin II Signaling in Lung Fibrosis Am. J. Respir. Cell Mol. Biol., December 1, 2007; 37(6): 640 - 650. [Abstract] [Full Text] [PDF]

				W. Song and S. Matalon Modulation of alveolar fluid clearance by reactive oxygen-nitrogen intermediates Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L855 - L858. [Full Text] [PDF]

				J. W. Lee, X. Fang, G. Dolganov, R. D. Fremont, J. A. Bastarache, L. B. Ware, and M. A. Matthay Acute Lung Injury Edema Fluid Decreases Net Fluid Transport across Human Alveolar Epithelial Type II Cells J. Biol. Chem., August 17, 2007; 282(33): 24109 - 24119. [Abstract] [Full Text] [PDF]

				A. Zakrzewicz, F. M. Kouri, B. Nejman, G. Kwapiszewska, M. Hecker, R. Sandu, E. Dony, W. Seeger, R. T. Schermuly, O. Eickelberg, et al. The transforming growth factor-{beta}/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension Eur. Respir. J., June 1, 2007; 29(6): 1094 - 1104. [Abstract] [Full Text] [PDF]

				R. E. Morty, B. Nejman, G. Kwapiszewska, M. Hecker, A. Zakrzewicz, F. M. Kouri, D. M. Peters, R. Dumitrascu, W. Seeger, P. Knaus, et al. Dysregulated Bone Morphogenetic Protein Signaling in Monocrotaline-Induced Pulmonary Arterial Hypertension Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1072 - 1078. [Abstract] [Full Text] [PDF]

				M. A. Alejandre-Alcazar, G. Kwapiszewska, I. Reiss, O. V. Amarie, L. M. Marsh, J. Sevilla-Perez, M. Wygrecka, B. Eul, S. Kobrich, M. Hesse, et al. Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L537 - L549. [Abstract] [Full Text] [PDF]

				H. G. Folkesson and M. A. Matthay Alveolar Epithelial Ion and Fluid Transport: Recent Progress Am. J. Respir. Cell Mol. Biol., July 1, 2006; 35(1): 10 - 19. [Full Text] [PDF]

				J. M. Hickman-Davis, C. McNicholas-Bevensee, I. C. Davis, H.-P. Ma, G. C. Davis, C. A. Bosworth, and S. Matalon Reactive Species Mediate Inhibition of Alveolar Type II Sodium Transport during Mycoplasma Infection Am. J. Respir. Crit. Care Med., February 1, 2006; 173(3): 334 - 344. [Abstract] [Full Text] [PDF]

				S. Matalon and S. I. Rennard Thrombin Increases Lung Water by Decreasing Na,K-ATPase Activity Am. J. Respir. Cell Mol. Biol., October 1, 2005; 33(4): 317 - 318. [Full Text] [PDF]