Wolf Norman, Penn Philip, Pendergrass William, Van Remmen Holly, Bartke Andrzej, Rabinovitch Peter, Martin George M
Department of Pathology, University of Washington School of Medicine, Box 3557470, University of Washington, Seattle, WA 98195-7470, USA.
Exp Eye Res. 2005 Sep;81(3):276-85. doi: 10.1016/j.exer.2005.01.024.
Five mouse models with known alterations of resistance to oxidative damage were compared by slit lamp examination for the presence and degree of advancement of age-related cataract in young adult and old animals along with wild type controls. A group of young and old normal C57BL/6Jax mice were examined first to constitute a standard, and they were found to exhibit age-related cataract development. Following this, four models on the C57BL/6 background with imposed genetic alterations affecting anti-oxidant enzyme presence or activity, and one outbred model in which a deletion blocked the growth hormone/IGF-1 axis, were similarly examined. There was no evidence of foetal or juvenile cataract development in any of these models, and an age-related severity for lens opacities was shown between young adult and old mice in all groups. Model 1, mice null for the anti-oxidant gene glutathione peroxidase-1 (GPX1) had significantly advanced cataracts in older mice vs. same age controls. In mouse model 2 hemizygous knockout of SOD2 (MnSOD) did not affect age-related cataract development. In model 3 combining the GPX1 and SOD2 deficiencies in the same animal did not advance cataract development beyond that of the GPX1 null alone. In model 4 the addition of anti-oxidant protection in the lens by transfection of human catalase targeted only to the mitochondria resulted in a significant delay in cataract development. The 5th model, growth hormone receptor knockout (GHR-/-) mice, also demonstrated a significant reduction in age-related cataract development, as well as dwarfism. These findings, in general, support the oxidative theory of age-related cataract development. The exception, the partial deletion of SOD2 in the hemizygous KO model, probably did not represent a sufficiently severe deprivation of anti-oxidant protection to produce pathologic changes in the lens.
通过裂隙灯检查，比较了五只已知抗氧化损伤抗性改变的小鼠模型以及野生型对照在年轻成年和老年动物中年龄相关性白内障的存在情况和进展程度。首先检查了一组年轻和年老的正常C57BL/6Jax小鼠以建立一个标准，发现它们呈现出年龄相关性白内障的发展。在此之后，同样检查了四个C57BL/6背景下具有影响抗氧化酶存在或活性的基因改变的模型，以及一个因缺失而阻断生长激素/胰岛素样生长因子-1轴的远交系模型。在这些模型中均未发现胎儿或幼年白内障发展的证据，并且所有组的年轻成年和老年小鼠之间晶状体混浊均显示出与年龄相关的严重程度。模型1，抗氧化基因谷胱甘肽过氧化物酶-1（GPX1）缺失的小鼠在老年小鼠中与同年龄对照相比白内障明显进展。在小鼠模型2中，超氧化物歧化酶2（MnSOD）的半合子敲除不影响年龄相关性白内障的发展。在模型3中，在同一只动物中同时缺乏GPX1和SOD2并没有使白内障发展超过单独缺乏GPX1的情况。在模型4中，通过仅靶向线粒体转染人过氧化氢酶在晶状体中添加抗氧化保护导致白内障发展显著延迟。第五个模型，生长激素受体敲除（GHR-/-）小鼠，也显示出年龄相关性白内障发展显著减少，以及侏儒症。总体而言，这些发现支持年龄相关性白内障发展的氧化理论。例外情况是，半合子敲除模型中SOD2的部分缺失可能并未代表抗氧化保护的严重缺乏，不足以在晶状体中产生病理变化。
