Environmental O2 is commonly used in the treatment of respiratory distress in the neonate, but detrimental effects of oxygen exposure can occur. One of the organ systems demonstrating pathologic changes is the vasculature of the retina. The acute phase is associated with morphologic alterations in the vascular intima, vasoconstriction, thrombus formation and occlusion of the vascular lumen. This acute phase is followed by a chronic phase of neovascularization leading to the clinically recognized syndrome of retrolental fibroplasia (RLF) also known as the retinopathy of prematurity (ROP). ROP causes 400 to 450 cases of blindness in the U.S. per year. Since prostacyclin (PGI2) is a potent vasodilator and inhibitor of thrombus formation, we reason that the crucial changes seen in the acute phase of oxygen toxicity may result from inhibition of formation of this potent prostaglandin. We have found that exposure of human umbilical vessels to hyperoxia results in significant inhibition in the ability of these vessels to produce PGI2. In further studies we have shown that other arachidonic acid metabolites known as hydroxyacids (HETEs) are produced by endothelial cells and affect endothelial cell migration, a major step in the process of neovascularization. Thus the pathology of both the acute and chronic phases of the retinopathy of prematurity appear consistent with the local liberation of arachidonic acid metabolites including the prostaglandins and hydroxyacids. Since these metabolites are produced at the cellular level, initial studies will focus on this problem in in vitro endothelial cell systems. Using endothelial cell cultures from aorta and retinal capillaries, the step(s) in arachidonic acid metabolism affected by varying oxygen tensions will be determined and the prostaglandins and hydroxyacids produced will be characterized. The effects of arachidonic acid metabolites found to be altered by endothelial cell oxygen exposure on various endothelial cell functions known to be important in neovascularization (i.e. protease production, migration and proliferation) will then be assessed. Varying O2 tensions may precipitate biochemical events at the cellular level which play an important role in the pathophysiology of this syndrome. A more complete understanding of these biochemical events should lead to a better understanding of ROP and thereby suggest avenues for its prevention.
| Graeber, J E; Glaser, B M; Setty, B N et al. (1990) 15-Hydroxyeicosatetraenoic acid stimulates migration of human retinal microvessel endothelium in vitro and neovascularization in vivo. Prostaglandins 39:665-73 |
