Pathogenesis and treatments for age-related macular degeneration

我们对10例老年性黄斑变性(AMD)患者手术切除的脉络膜新生血管(CNV)膜进行了免疫组织化学染色。并用免疫组织化学方法在CNV膜上检测到氧化型脂蛋白。表达清道夫受体的细胞主要是巨噬细胞，少量RPE。在CNV膜上均检测到SR-PSOX和LOX-1mRNAs。然后，我们调查了正常眼睛中是否存在氧化磷脂，以及氧化磷脂水平是否随着年龄的增长而变化。免疫组织化学结果显示，氧化磷脂酰胆碱存在于正常人黄斑区的光感受器和视网膜色素上皮中，且其水平随年龄的增长而增加。与年龄匹配的正常眼相比，AMD患者眼表现出更强的氧化磷脂免疫反应。我们用蓝光照射诱导小鼠视网膜氧化磷脂，并比较2月龄和12月龄C57/BL6小鼠的反应。我们发现，视网膜中诱导的氧化磷脂随年龄增加而增加，氧化磷脂可刺激RPE中单核细胞趋化蛋白-1(MCP-1)的表达。然后，我们将氧化磷脂注入视网膜下腔，发现MCP-1和CNV的形成速度很快。MCP-1基因敲除或CCR-2基因敲除的小鼠未发现CNV的形成。我们的研究结果提示，衰老可能使视网膜受到氧化应激和氧化磷脂的影响，MCP-1可能在AMD的发病机制中发挥重要作用。

We performed immunohistochemistry on 10 surgically-excised choroidal neovascular (CNV) membranes from eyes with age-related macular degeneration (AMD). and found oxidized lipoproteins were immunohistochemically detected in the CNV membranes. Cells expressing scavenger receptors were found to be predominantly macrophages with a minority of RPE. Both SR-PSOX and LOX-1 mRNAs were detected in CNV membranes. We, then, investigated whether oxidized phospholipids were present in normal eyes and whether the level changed with increasing age. Immunohistochemistry showed that oxidized phosphatidylcholine was present in the photoreceptors and retinal pigment epithelium of the normal human macular area, and their levels increased with age. Eyes with AMD showed more intense immunoreactivity for oxidized phospholipids than age-matched normal eyes.We induced oxidized phospholipids in mice retina with blue light irradiation, and compared reactions between 2-and 12-month-old C57/BL6 mice. We found that induced oxidized phospholipids in the retina increase with age and oxidized phospholipids may stimulate expression of monocyte chemotactic protein-1 (MCP-1) in the RPE. We, then, injected oxidized phospholipids into the subretinal space and found increase of MCP-1 and CNV formation at high rate. Mice with MCP-1 knockout or Ccr-2 knockout showed no formation of CNV. Our findings suggest that aging may make the retina subjected to oxidative stress and oxidized phospholipids and MCP-1 may play an important role in AMD pathogenesis.