Exposure to O2 is used to treat neonatal respiratory distress. Detrimental effects of O2 exposure can occur. One organ system demonstrating pathologic changes is the retina. The acute phase is associated with vasoconstriction and occlusion of the vascular lumen. This acute phase is followed by a chronic phase of neovascularization the sum total of which leads to the high morbitity syndrome of retrolental fibroplasia (RLF) which causes 400 to 450 cases of blindness in the U.S. per year. Most recent evidence suggests that hypoxemia during recovery from O2 induced injury may precipitate more severe RLF. We have preliminary evidence that links hydroxyeicosatetraenoic acids (HETES) with angiogenesis. 15-HETE a product that we have shown is synthesized by human vessels enhances endothelial cell migration (the first step in the angiogenic process), while 12-HETE a platelet and lymphocyte product is inhibitory. Moreover, in 2 pathologic conditions associated with abnormal angiogenesis we have data demonstrating an increase in vascular 15-HETE (in vitro hypoxemia, and in vivo in the umbilical vessels from infants of diabetic mothers). We propose to expand these findings further. Important HETES that are produced in vivo will be evaluated for pro or anti-angiogenic effects. HETES evaluated will include 5,8,9,11,12 and 15-HETE, 5-12 and 8-15 diHETE, and the Leukotrienes. Since HETES affecting angiogenesis should be made either by blood vessels or by formed elements passing through them, we will characterize HETES in tissues pertinent to our proposal i.e. human vessels and endothelium, human smooth muscle cells, red cells, capillary endothelium and kitten retinal endothelial cells. We will next study the effects of hypoxia, hyperoxia/hypoxia, or hyperoxia alone on HETE production in vitro (cell cultures) and in vivo. An increase in proangiogenic plus and minus a decrease in antiangiogenic HETES is hypothesized. Neonates will also be evaluated for the production of circulating blood HETE levels. Finally, we will turn our attention to the initial phase of RLF i.e. vasoconstriction and vasoocclusion. We have observed in vitro that hyperoxia inhibits prostacyclin (a metabolite that is antiaggregatory and vasodilatory). We will evaluate retinal prostacyclin production in animals immediately post hyperoxia. If local inhibition is found to occur, then further in vitro studies will elucidate the mechanisms involved in this inhibition.
| Setty, B N; Ganley, C; Stuart, M J (1985) Effect of changes in oxygen tension on vascular and platelet hydroxyacid metabolites. II. Hypoxia increases 15-hydroxyeicosatetraenoic acid, a proangiogenic metabolite. Pediatrics 75:911-5 |
