| Phagocytosis of the rod outer segment (ROS) by the retinal pigment endothelium (RPE) is proposed to respond to oxidative damage of retina. To examine this idea, a group of oxidatively truncated phospholipids derived from arachidonoyl, linoleoyl, and docosahexaenoyl phosphatidylcholine were synthesized. The synthetic phospholipids had no effects on the binding of ROS to RPE. However they did inhibit up to 45% of the intake of ROS by RPE. CD36 null RPE cells retain their phagocytotic capacity, however they lack the ability to respond to oxidized phospholipids. This indicates that RPE cells recognize oxidized phospholipids through the receptor CD36. Oxidized phospholipids were shown, by LC-MS, to be present in the oxidation product mixture from docosahexaenoyl phosphatidylcholine radiated with UVA by using LC-MS. Light exposure also promoted the production of oxidized phospholipids in rat retina in vivo. Therefore it is proposed that oxidation of ROS lipids, especially docosahexaenoyl phospholipids, promote phagocytosis of shed ROS tips via CD36 receptors in the eye. Since the level of both lipid peroxidation and protein nitration were elevated in light exposed rat retina in vivo, it is proposed that peroxynitrate may promote light induced retinal lipid peroxidation in vivo.; 9-Hydroperxy-10,12-octadienoic acid and 13-hydroperxy-9,11-octadienoic acid are the primary initial oxidation products from linoleic acid. They can fragment to produce oxidatively truncated lipids including γ-hydroxyalkenals, such as 9-hydroxy 12-oxo-10(E)-dodecenoic acid (HODA) and 4-hydroxy-2-nonenal (HNE). Many mechanisms and putative intermediates have been proposed for the fragmentation of hydroperoxydienes, however there is little experimental evidence for any of these mechanisms. By examining the autoxidation of one of the putative intermediates, 13-hydroperoxy-9,10-cis-epoxyoctadeca-11-enoic acid, we concluded that the proposed epoxy hydroperoxide mechanism involving this intermediate is not a major pathway to produce γ-hydroxy alkenals from hydroperoxydienes. We also discovered that 9-hydroxy-10,12-octadienoic acid produced HODA but not HNE, and that 13-hydroxy-9,11-octadienoic acid produced FINE but not HODA upon autoxidation in the presence of a hydroperoxide. HODA and its fragmentation product 9-oxononanoic acid can be further oxidized to 4-hydroxydodec-2-enedioic acid and azeleic acid respectively.; In addition to truncated lipids, lipid oxidation also produces iso-levuglandins that can react with proteins to form hydroxylactams. A one-pot synthese of 2,3-unsymmetrically disubstituted maleimides was developed to prepare the key intermediates for a total synthesis of such hydroxylactams. |
