Previous studies have documented the role of inflammatory mediators (e.g., TNF, IL-6), hemostatic mediators (e.g. tissue factor/VIIa), hemostatic regulators (e.g. proteins C and S), and hemostatic modulators (e.g C4b binding protein) in driving and controlling the baboon response to E. coli. The anti-inflammatory effects of the hemostatic regulators particularly those of the protein C system, and the recent discovery of the involvement of the endothelial protein C receptor (EPCR) and thrombin activated fibrinolytic inhibitor (TADI) in this system, have led us to study their contribution to its anti-inflammatory and anticoagulant properties. EPCR is the newest member of the endothelial/protein C network and it, like protein C itself, is essential in controlling the response to E. coli. The form of EOCR is unique in that while it inhibits protein C anticoagulant activity in vitro it also inhibits tight neutrophil/endothelial cell interactions under flow conditions. We plan to examine the pathophysiologic relevance of these in vitro observations in primate non-inflammatory (thrombin) and inflammatory (E. Coli) models of DIC. TAFI, the newest member of fibrinolytic inhibitors which are connected to the protein C network, also is unique in that, (1) while it is activated by the thrombin/thrombomodulin complex, its formation is down regulated by activated protein C which also is generated by this complex, (2) it is a carboxypeptidase with potential anti-inflammatory as well as antifibrinolytic activity. Again the relevance of these in vitro observations is unknown, nor is it known under what pathophysiologic conditions TAFI comes into play. We plan to examine TAFI function in the primate models noted above as well as in the C4bBP/sublethal E. coli model of microvascular thrombosis. Finally, we recently found that the endothelial/protein C network of diabetic baboons failed to mount an anticoagulant response to fXaPCPS. It was only the fibrinolytic """"""""back up"""""""" response that saved these animals. We plan to determine which components of the protein C system are responsible for this failure and in addition to assess what effect this diabetic deficiency has on the endothelial susceptibility to inflammatory stress (e.g., TNF, IL-6).
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