MODULATION OF HUMAN ENDOTHELIAL THROMBOMODULIN BY NEUTROPHILS AND THEIR RELEASE PRODUCTS

Pulmonary microvascular injury, one of the earliest events in adult re spiratory distress syndrome (ARDS), is caused by the release of injuri ous products from stimulated neutrophils and other inflammatory cells in the lung microvessels. An increased level of the endothelial cell-s urface anticoagulant protein thrombomodulin (TM) in plasma from patien ts with ARDS as shown in this study may be one consequence of this, an d our objective in this investigation was to define the mechanisms by which TM is modulated by neutrophils, using an endothelial tissue cult ure system. Human neutrophils in contact with endothelium caused a fou rfold reduction in cell-surface TM activity, but only after prior neut rophil priming and activation. Neutrophil release products elastase an d cathepsin G caused rapid dose-related reductions in endothelial cell -surface TM activity, with complete abolition at 5 mu g/ml in the abse nce of endothelial detachment. H2O2 also reduced TM activity. TM antig en accumulated in culture supernatant after treatment of endothelium w ith cathepsin G, indicating proteolytic release of cell-surface TM. We conclude that primed activated neutrophils are potent modulators of e ndothelial TM in vitro.