Preeclampsia is a health problem of pregnancy that affects approximately 7-10 percent women and is associated with significant maternal/neonatal morbidity and mortality. It is characterized by vascular endothelial, hepatic and renal glomerular cell dysfunction. The placenta is thought to produce factors that result in the pathogenesis of the disease since delivery of the placenta is an effective cure. Unfortunately, the identity and role of these placental factors in the pathogenesis of preeclampsia is poorly understood. Thrombotic Thrombocytopenia Purpura (TTP) and Hemolytic Uremic Syndrome (HUS), two diseases that are clinically similar to preeclampsia, are caused by Fas/Fas ligand (FasL) induced microvascular endothelial cell apoptosis. Resent studies in our laboratory have demonstrated that FasL expression in placental trophoblast is an important mediator of maternal immune tolerance to the fetus. We also have preliminary evidence that preeclampsia is associated with increased placental FasL production and secretion into the maternal circulation. Taken together, these findings suggest an important role for Fas/FasL as a mechanism in the pathogenesis of preeclampsia. Specifically, our hypothesis states that preeclampsia is associated with increased levels of circulating FasL resulting in apoptosis of microvascular endothelial, hepatic, and renal glomerular cells. Furthermore, Th1 cytokines and lipid peroxides which are increased in preeclampsia may augment Fas/FasL mediated apoptosis in these target cells. These hypotheses will be tested with regards to the following specific aims: 1. To determine the sources involved in the increased expression and systemic delivery of FasL in preeclampsia. 2. To evaluate the regulation of FasL expression by hypoxia, maternal lymphocyte and placental derived cytokines. 3. To determine the role of Fas mediated cell apoptosis in the pathophysiology of preeclampsia. These studies will significantly advance our understanding of the mechanisms involved in the pathogenesis of preeclampsia and provide new rationales for the treatment of this disease.
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