Tumor necrosis factor-α–dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability

• Published in: Blood Vol. 105; no. 9; pp. 3569 - 3576
• Main Authors: Seybold, Joachim, Thomas, Dirk, Witzenrath, Martin, Boral, Şengül, Hocke, Andreas C., Bürger, Alexander, Hatzelmann, Armin, Tenor, Hermann, Schudt, Christian, Krüll, Matthias, Schütte, Hartwig, Hippenstiel, Stefan, Suttorp, Norbert
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.05.2005; The Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; Capillary Permeability - drug effects; Cell physiology; Cyclic Nucleotide Phosphodiesterases, Type 2; Edema - chemically induced; Endothelium, Vascular - cytology; Endothelium, Vascular - enzymology; Female; Fundamental and applied biological sciences. Psychology; Humans; In Vitro Techniques; Lung - pathology; Membrane and intracellular transports; Mice; Mice, Inbred BALB C; Molecular and cellular biology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Sepsis - pathology; Thrombin - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; Umbilical Veins - cytology; Up-Regulation - drug effects; Up-Regulation - genetics; Endothelial cell; Deoxyribose-phosphate aldolase; Lung; Thrombin; Lyases; Sepsis syndrome; Tumor necrosis factor α; Human; Edema; Serine endopeptidases; Cell permeability; Enzyme; Rodentia; Cyclic AMP; 3',5'-GMP; Aldehyde-lyases; Gene expression; Infection; Peptidases; Carbon-carbon lyases; Vertebrata; Mammalia; Adult respiratory distress syndrome; Mouse; Cyclic nucleotide; Hydrolases
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-07-2729

The pleiotropic cytokine tumor necrosis factor-α (TNF-α) 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-α 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-α stimulation, while PDE3 and PDE4 activities remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF-α 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-α–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).