RICKETTSIAL EFFECTS ON ENDOTHELIAL PROCOAGULANT ACTIVITY

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Vascular endothelial cells grown in vitro have been widely used as model systems for investigations of the in vivo function of these cells as an anti-thrombocytic barrier. Perturbation of the cultured endothelial cells by soluble agents such as cytokines, lipopolysaccharide, enzymes, immune and physical injury are thought to induce prothrombocytic alterations in these cells which resemble those occurring in vivo. These changes include production of tissue factor, down regulation of thrombomodulin, release of von Willebrand factor, and enhanced platelet adherence. However, there is little direct experimental evidence correlating these endothelial cell alterations and actual thrombus formation in vivo. The purpose of this application is to use the spotted fever group rickettsia, Rickettsia akari, as a precise probe of endothelial cell prothrombocytic changes in cultured endothelial cells, ex vivo in human umbilical cord veins, and in vivo in an experimental C3H/HeJ mouse model. Rickettsiae primarily infect the vascular endothelium resulting in a localized inflammatory response and formation of focal thromboses which induce organ disfunction and occasionally fatal outcome in humans. Initially the nature and time course of prothrombocytic alterations caused by rickettsial infection of cultured endothelial cells will be determined and compared with inflammatory stimuli such as interleukin-1, tumor necrosis factor alpha and lipopolysaccharide. The effects of rickettsial infection on tissue factor and thrombomodulin expression, and platelet adherence properties of cultured endothelial cells will be extensively characterized. Once these changes are understood, the changes induced by rickettsial infection in endothelial cells in the ex vivo umbilical cord model and in the in vivo mouse model will be determined to see if they are comparable. If successful, the study would validate the relevance of the in vitro endothelial cell culture system as a mirror of in vivo thrombotic disease.