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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3569-3576. Prepublished online as a Blood First Edition Paper on January 13, 2005; DOI 10.1182/blood-2004-07-2729. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2729v1 105/9/3569    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Seybold, J. Articles by Suttorp, N. Search for Related Content PubMed PubMed Citation Articles by Seybold, J. Articles by Suttorp, N. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Tumor necrosis factor-–dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability Joachim Seybold, Dirk Thomas, Martin Witzenrath, engül Boral, Andreas C. Hocke, Alexander Bürger, Armin Hatzelmann, Hermann Tenor, Christian Schudt, Matthias Krüll, Hartwig Schütte, Stefan Hippenstiel, and Norbert Suttorp From the Charité Universitätsmedizin Berlin, Humboldt-University, Department of Internal Medicine/Infectious Diseases, Berlin, Germany; and Altana Pharma, Konstanz, Germany. The pleiotropic cytokine tumor necrosis factor- (TNF-) and thrombin lead to increased endothelial permeability in sepsis. Numerous studies demonstrated the significance of intracellular cyclic nucleotides for the maintenance of endothelial barrier function. Actions of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are terminated by distinct cyclic nucleotide phosphodiesterases (PDEs). We hypothesized that TNF- could regulate PDE activity in endothelial cells, thereby impairing endothelial barrier function. In cultured human umbilical vein endothelial cells (HUVECs), we found a dramatic increase of PDE2 activity following TNF- stimulation, while PDE3 and PDE4 activities remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF- increased PDE2 expression in a p38 mitogen-activated protein kinase (MAPK)–dependent manner. Endothelial barrier function was investigated in HUVECs and in isolated mice lungs. Selective PDE2 up-regulation sensitized HUVECs toward the permeability-increasing agent thrombin. In isolated mice lungs, we demonstrated that PDE2 inhibition was effective in preventing thrombin-induced lung edema, as shown with a reduction in both lung wet-to-dry ratio and albumin flux from the vascular to bronchoalveolar compartment. Our findings suggest that TNF-–mediated up-regulation of PDE2 may destabilize endothelial barrier function in sepsis. Inhibition of PDE2 is therefore of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS). CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R.C. Werthmann, K. von Hayn, V.O. Nikolaev, M.J. Lohse, and M. Bünemann Real-time monitoring of cAMP levels in living endothelial cells: thrombin transiently inhibits adenylyl cyclase 6 J. Physiol., August 15, 2009; 587(16): 4091 - 4104. [Abstract] [Full Text] [PDF] B. Temmesfeld-Wollbruck, B. Brell, C. zu Dohna, M. Dorenberg, A. C. Hocke, H. Martens, J. Klar, N. Suttorp, and S. 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