Hemophiliacs develop recurrent joint bleeds, leading to chronic joint symptomatology and disability. In the early stage of hemophilic arthropathy neovascularization of the synovium occurs, which leads to a cycle of rebleeding, greater degrees of proliferative changes, and siderosis. Neovascularization appears to be a crucial phase of early hemophilic arthropathy setting the stage for rebleeding and initiation of the chronic joint disease that evolves. We hypothesize that in hemophilic arthropathy synovial tissues and fluid produce increased amounts of proangiogenic and decreased amounts of normally occurring antiangiogenic metabolites such that abnormal synovial- neovascularization is favored. In preliminary work (n-6) we have found that hemophilic synovial tissues and fluids produce increased amounts of 15-HETE and LTB4, compounds we have shown to be proangiogenic. In contrast the major hydroxyacid observed in control (noninflammatory) arthritis is 12-HETE an eicosanoid we found to be antiangiogenic. Other qualitative and quantitative differences in eicosanoid product were also observed. Controls produced increased amounts of prostaglandins (6KPGF1 alpha, PGD2, PGE2 and PGF2 alpha) when compared to hemophilic joints. Qualitative differences in HETE production occurred. Whereas hemophilic tissues produced LTB4, 15-HETE, 11-HETE, 5-HETE, 8,15 di-HETE, 5, 12 di-HETE, and HHT, controls produced 12-HETE as the major product. We propose to expand these promising preliminary observations by a systematic evaluation of eicosanoid production (prostaglandins, HETEs and leukotrienes) in the synovial tissues and fluid of patients with hemophilic arthropathy when compared to other control (non-inflammatory) arthritis. We will ascertain the pro or antiangiogenic properties of these compounds in various in vitro and in vivo angiogenic assays. The effects of these eicosanoids on fibroblast and synovial cell proliferation will also be assessed. Eicosanoid production in an animal model of hemophilic arthropathy will be evaluated in relation to synovial neovascularization. A final test of the pro or antiangiogenic properties of the compounds identified will be the injection of these eicosanoids (singly or in combinations) intraarticularly into control animal joints. The studies proposed should elucidate the role of eicosanoids in hemophilic arthropathy. The project could lead to the use of inhibitors of cyclooxygenase, lipoxygenase, or leukotriene biosynthesis in an attempt to modulate the animal (and ultimately) hemophilic-induced arthropathy.
| Setty, B N; Werner, M H; Hannun, Y A et al. (1992) 15-Hydroxyeicosatetraenoic acid-mediated potentiation of thrombin-induced platelet functions occurs via enhanced production of phosphoinositide-derived second messengers--sn-1,2-diacylglycerol and inositol-1,4,5-trisphosphate. Blood 80:2765-73 |
| Setty, B N; Dampier, C D; Stuart, M J (1992) 1-Deamino-8 D-arginine vasopressin decreases the production of 13-hydroxyoctadecadienoic acid by endothelial cells. Thromb Res 67:545-58 |
