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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 16, 2004 Accepted January 3, 2005 Tumor necrosis factor- dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability Joachim Seybold*, Dirk Thomas, Martin Witzenrath, Sengul Boral, Andreas C Hocke, Alexander Burger, Armin Hatzelmann, Hermann Tenor, Christian Schudt, Matthias Krull, Hartwig Schutte, Stefan Hippenstiel, and Norbert Suttorp Department of Internal Medicine / Infectious Diseases, Charite Universitatsmedizin Berlin, Humboldt-University, Berlin, Germany Altana Pharma AG, Konstanz, Germany * Corresponding author; email: joachim.seybold{at}charite.de. 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 AMP and cyclic GMP are terminated by distinct cyclic nucleotide phosphodiesterases (PDE). We hypothesized that TNF- could regulate PDE activity in endothelial cells thereby impairing endothelial barrier function. In cultured human umbilical vein endothelial cells (HUVEC) 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 MAPK dependent manner. Endothelial barrier function was investigated in HUVECs and in isolated mice lungs. Selective PDE2 upregulation sensitized HUVECs towards 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 upregulation 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. Hippenstiel Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G43 - G51. [Abstract] [Full Text] [PDF] I. Diebold, T. Djordjevic, A. Petry, A. 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