HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Tumor necrosis factor-–dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability

The pleiotropic cytokine tumor necrosis factor- (TNF-) and thrombin lead to increased endothelial permeability in sep-sis. Numerous studies demonstrated the significance of intracellular cyclic nucleo-tides for the maintenance of endothelial barrier function. Actions of cyclic adeno-sine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are terminated by distinct cyclic nucleotide phosphodiesterases (PDEs). We hypoth-esized that TNF- could regulate PDE activity in endothelial cells, thereby im-pairing endothelial barrier function. In cultured human umbilical vein endothe-lial cells (HUVECs), we found a dramatic increase of PDE2 activity following TNF- stimulation, while PDE3 and PDE4 activi-ties remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF- increased PDE2 expression in a p38 mitogen-acti-vated 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 permeabil-ity-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 endo-thelial barrier function in sepsis. Inhibi-tion of PDE2 is therefore of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS)