Macrophages inhibit neovascularization in a murine model of age-related macular degeneration.
Macrophages inhibit neovascularization in a murine model of age-related macular degeneration.
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DOI：
10.1371/journal.pmed.0030310
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发表时间：
2006-08
期刊：
影响因子：
15.8
通讯作者：
Ferguson, Thomas A.
中科院分区：
文献类型：
--
作者：
Apte, Rajendra S.;Richter, Jennifer;Herndon, John;Ferguson, Thomas A.
视网膜相关性黄斑变性（AMD）是至少三大洲50岁以上人群失明的主要原因。脉络膜新生血管（CNV）是视网膜下异常血管发育的过程。CNV在10%的AMD患者中发展，但占AMD失明的90%。虽然AMD中CNV的确切病因仍然未知，但已显示促进肿瘤生长并支持动脉粥样硬化斑块形成的炎症反应的巨噬细胞组分被认为刺激致盲性眼病中的异常血管生成。目前的理论是巨噬细胞浸润促进CNV中新生血管的发展。我们研究了巨噬细胞在CNV小鼠模型中的作用。IL-10 −/−小鼠对各种刺激的反应增加了炎症，与野生型相比，CNV显著减少，巨噬细胞浸润增加。防止巨噬细胞进入眼睛促进新生血管形成，而直接注射巨噬细胞显着抑制CNV。巨噬细胞的抑制作用由TNF家族死亡分子Fas配体（CD 95-配体）介导。免疫血管相互作用可以是高度复杂的。正常的巨噬细胞功能在控制眼睛中的病理性新血管形成中是至关重要的。IL-10调节眼睛中的巨噬细胞活性，并且是一种有吸引力的治疗靶点，以抑制AMD中的CNV，否则CNV可能导致失明。Apte及其同事研究了巨噬细胞在脉络膜新生血管小鼠模型中的作用，并表明正常的巨噬细胞功能在控制眼部病理性新生血管中至关重要。在发达国家，老年人视力下降的最常见原因是年龄相关性黄斑变性（AMD）。黄斑是视网膜的中心部分（眼睛后部的膜状膜），对于敏锐的中心视觉来说是最敏感和最重要的。存在两种类型的晚期AMD：所谓的湿性或新生血管性AMD（新生血管性意味着“新血管”）和干性或地图状萎缩AMD（萎缩意味着“消耗掉”）。湿性AMD发生时，异常，脆弱的新血管生长在视网膜后面的黄斑下。这些血管经常泄漏血液和液体，从而提升黄斑。干性AMD发生在黄斑（视杆细胞和视锥细胞）中的光敏细胞分解时。为了进一步研究这种疾病，研究人员使用动物模型。一种这样的动物模型是通过使用激光损伤小鼠的眼睛后部来制造的，这会导致新血管的形成。然后可以测试各种治疗方法，看看它们是否对损伤有任何影响。关于AMD的一种理论是，免疫系统可能参与决定眼睛后部的损伤有多严重，以及有多少新血管形成。研究人员想看看免疫系统对AMD的影响，特别是一种称为巨噬细胞的细胞和一种从骨髓细胞分泌的物质IL-10的影响，这会影响这些巨噬细胞的工作方式。研究人员使用了一种缺乏IL-10的小鼠品系，在模拟AMD的眼睛中诱导损伤，然后观察巨噬细胞在眼睛异常中的作用。他们发现，在缺乏IL-10的小鼠眼中，与IL-10含量正常的小鼠相比，新血管形成减少，巨噬细胞数量增加。此外，通过向眼睛注射IL-10来防止巨噬细胞进入这些小鼠的眼睛，使新血管形成变得更糟，而直接注射巨噬细胞则使其变得更好。虽然动物模型不能完全复制人类的疾病，但它们可以让我们了解疾病是如何发生的，并提出可能的治疗策略。抑制IL-10的作用或其他使巨噬细胞在眼睛中更有效的策略可能是AMD的有效治疗。在相关的《透视》（DOI：10.1371/journal.pmed.0030364）中，苏珊·莱特曼和弗吉尼亚·考尔德进一步讨论了这些发现，包括建议下一步需要做的新实验。请通过http://dx.doi.org/10.1371/journal.pmed.0030310上的本摘要在线版本访问这些网站。关于黄斑变性的MedlinePlus百科全书条目美国国立卫生研究院老年健康信息页面AMD国家眼科研究所AMD事实页面
Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 y of age in at least three continents. Choroidal neovascularization (CNV) is the process by which abnormal blood vessels develop underneath the retina. CNV develops in 10% of patients with AMD but accounts for up to 90% of the blindness from AMD. Although the precise etiology of CNV in AMD remains unknown, the macrophage component of the inflammatory response, which has been shown to promote tumor growth and support atherosclerotic plaque formation, is thought to stimulate aberrant angiogenesis in blinding eye diseases. The current theory is that macrophage infiltration promotes the development of neovascularization in CNV. We examined the role of macrophages in a mouse model of CNV. IL-10 −/− mice, which have increased inflammation in response to diverse stimuli, have significantly reduced CNV with increased macrophage infiltrates compared to wild type. Prevention of macrophage entry into the eye promoted neovascularization while direct injection of macrophages significantly inhibited CNV. Inhibition by macrophages was mediated by the TNF family death molecule Fas ligand (CD95-ligand). Immune vascular interactions can be highly complex. Normal macrophage function is critical in controlling pathologic neovascularization in the eye. IL-10 regulates macrophage activity in the eye and is an attractive therapeutic target in order to suppress or inhibit CNV in AMD that can otherwise lead to blindness. Apte and colleagues examined the role of macrophages in a mouse model of choroidal neovascularization, and showed that normal macrophage function is critical in controlling pathologic neovascularization in the eye. The most common cause of poor eyesight in later life in the developed world is known as age-related macular degeneration (AMD). The macula is the central part of the retina (the film-like membrane at the back of the eye), which is the most sensitive and important for sharp central vision. There are two types of advanced AMD: so-called wet, or neovascular, AMD (neovascular means “new vessel”) and dry, or geographic atrophy, AMD (atrophy means “to waste away”). Wet AMD occurs when abnormal, fragile new blood vessels grow under the macula behind the retina. These blood vessels often leak blood and fluid, which lift the macula. Dry AMD occurs as the light-sensitive cells in the macula (the rods and cones) break down. To study this disease further, researchers use animal models. One such animal model is made by using a laser to damage the back of the eye in a mouse, which causes the formation of new vessels. Various treatments can then be tested to see if they have any effect on the damage. One theory about AMD is that the immune system may be involved in determining how severe the damage at the back of the eye is, and how much new vessel formation occurs. The researchers wanted to look at the effect of the immune system on AMD, in particular, the effect of one type of cell called a macrophage, and a substance, IL-10, that is secreted from bone marrow cells and that affects how these macrophages work. The researchers used a mouse strain in which IL-10 was absent, induced damage in the eyes that mimicked AMD, and then looked at what role macrophages had in the eye abnormalities. They found that in the eyes of mice that lacked IL-10, there was reduced new vessel formation and increased numbers of macrophages compared to mice that had normal amounts of IL-10. Also, preventing macrophages from getting into the eyes of such mice by injecting IL-10 into the eyes made the new vessel formation worse, while direct injection of macrophages made it better. Although animal models cannot completely replicate disease in humans, they can give us an idea of how diseases might come about and suggest possible treatment strategies. It is possible that inhibiting the effect of IL-10, or other strategies that make macrophages more efficient in the eye, may be a useful treatment for AMD. In a related Perspective (DOI: 10.1371/journal.pmed.0030364), Susan Lightman and Virginia Calder discuss the findings further, including suggesting new experiments that will need to be done as a next step. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030310. MedlinePlus encyclopedia entry on macular degeneration National Institutes of Health Senior Health page of information on AMD National Eye Institute AMD fact page
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
4.2
作者：
Campochiaro, PA;Nguyen, QD;Wei, LL
通讯作者：
Wei, LL
影响因子：
4.4
作者：
Apte, RS;Barreiro, RA;Ferguson, TA
通讯作者：
Ferguson, TA
影响因子：
--
作者：
MILLER, JW;WALSH, AW;GRAGOUDAS, ES
通讯作者：
GRAGOUDAS, ES
影响因子：
--
作者：
Adamis, AP;Shima, DT;Miller, JW
通讯作者：
Miller, JW