Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Cell Sci. 2012 May 15;125(Pt 10):2407-15. doi: 10.1242/jcs.097683. Epub 2012 Feb 22.
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Although pathogenic factors, such as oxidative stress, inflammation and genetics are thought to contribute to the development of AMD, little is known about the relationships and priorities between these factors. Here, we show that chronic photo-oxidative stress is an environmental factor involved in AMD pathogenesis. We first demonstrated that exposure to light induced phospholipid oxidation in the mouse retina, which was more prominent in aged animals. The induced oxidized phospholipids led to an increase in the expression of monocyte chemoattractant protein-1, which then resulted in macrophage accumulation, an inflammatory process. Antioxidant treatment prevented light-induced phospholipid oxidation and the subsequent increase of monocyte chemoattractant protein-1 (also known as C-C motif chemokine 2; CCL2), which are the beginnings of the light-induced changes. Subretinal application of oxidized phospholipids induced choroidal neovascularization, a characteristic feature of wet-type AMD, which was inhibited by blocking monocyte chemoattractant protein-1. These findings strongly suggest that a sequential cascade from photic stress to inflammatory processes through phospholipid oxidation has an important role in AMD pathogenesis. Finally, we succeeded in mimicking human AMD in mice with low-level, long-term photic stress, in which characteristic pathological changes, including choroidal neovascularization formation, were observed. Therefore, we propose a consecutive pathogenic pathway involving photic stress, oxidation of phospholipids and chronic inflammation, leading to angiogenesis. These findings add to the current understanding of AMD pathology and suggest protection from oxidative stress or suppression of the subsequent inflammation as new potential therapeutic targets for AMD.
年龄相关性黄斑变性（AMD）是发达国家老年人致盲的主要原因。虽然氧化应激、炎症和遗传等致病因素被认为与 AMD 的发生发展有关，但这些因素之间的关系和优先级知之甚少。在这里，我们表明慢性光氧化应激是 AMD 发病机制中的一个环境因素。我们首先证明暴露于光线下会诱导小鼠视网膜中的磷脂氧化，而在老年动物中更为明显。诱导的氧化磷脂导致单核细胞趋化蛋白-1（MCP-1）的表达增加，进而导致巨噬细胞积累，引发炎症过程。抗氧化治疗可预防光诱导的磷脂氧化和随后的单核细胞趋化蛋白-1（也称为 C-C 基序趋化因子 2；CCL2）增加，这是光诱导变化的开始。氧化磷脂的视网膜下应用可诱导脉络膜新生血管形成，这是湿性 AMD 的一个特征性特征，而阻断单核细胞趋化蛋白-1可抑制其形成。这些发现强烈表明，从光应激到通过磷脂氧化的炎症过程的连续级联反应在 AMD 的发病机制中起重要作用。最后，我们成功地在低水平、长期光应激的小鼠中模拟了人类 AMD，观察到了包括脉络膜新生血管形成在内的特征性病理变化。因此，我们提出了一个连续的致病途径，涉及光应激、磷脂氧化和慢性炎症，导致血管生成。这些发现增加了对 AMD 病理的现有认识，并表明针对氧化应激的保护或随后炎症的抑制可能成为 AMD 的新潜在治疗靶点。
