Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration
Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration
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慢性光氧化应激和随后的 MCP-1 激活是年龄相关性黄斑变性的致病因素
DOI：
10.1242/jcs.097683
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发表时间：
2012-05-15
影响因子：
4
通讯作者：
Kamei, Motohiro
中科院分区：
文献类型：
--
作者：
Suzuki, Mihoko;Tsujikawa, Motokazu;Kamei, Motohiro
视网膜相关性黄斑变性（AMD）是发达国家老年人失明的主要原因。虽然致病因素，如氧化应激，炎症和遗传被认为有助于AMD的发展，但对这些因素之间的关系和优先级知之甚少。在这里，我们表明，慢性光氧化应激是一个环境因素参与AMD的发病机制。我们首先证明，暴露于光诱导小鼠视网膜中的磷脂氧化，这在老年动物中更为突出。诱导的氧化磷脂导致单核细胞趋化蛋白-1的表达增加，然后导致巨噬细胞积聚，这是一种炎症过程。抗氧化剂处理阻止了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; CCL 2）的增加，这是光诱导变化的开始。视网膜下应用氧化磷脂诱导脉络膜新生血管形成，这是湿性AMD的特征，可通过阻断单核细胞趋化蛋白-1来抑制。这些发现有力地表明，从光应激到炎症过程通过磷脂氧化的连续级联反应在AMD发病机制中具有重要作用。最后，我们成功地模仿人类AMD小鼠低水平，长期的光应激，其中观察到的特征性病理变化，包括脉络膜新生血管形成。因此，我们提出了一个连续的致病途径，涉及光应力，氧化磷脂和慢性炎症，导致血管生成。这些发现增加了目前对AMD病理学的理解，并建议保护免受氧化应激或抑制随后的炎症作为AMD的新的潜在治疗靶点。
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.