Shen Jikui, Yang Xiaoru, Dong Aling, Petters Robert M, Peng You-Wei, Wong Fulton, Campochiaro Peter A
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
J Cell Physiol. 2005 Jun;203(3):457-64. doi: 10.1002/jcp.20346.
Retinitis pigmentosa (RP) is a prevalent cause of blindness caused by a large number of different mutations in many different genes. The mutations result in rod photoreceptor cell death, but it is unknown why cones die. In this study, we tested the hypothesis that cones die from oxidative damage by performing immunohistochemical staining for biomarkers of oxidative damage in a transgenic pig model of RP. The presence of acrolein- and 4-hydroxynonenal-adducts on proteins is a specific indicator that lipid peroxidation has occurred, and there was strong immunofluorescent staining for both in cone inner segments (IS) of two 10-month-old transgenic pigs in which almost all rods had died, compared to faint staining in two 10-month-old control pig retinas. In 22- and 24-month-old transgenic pigs in which all rods and many cones had died, staining was strong in cone axons and some cell bodies as well as IS indicating progression in oxidative damage between 10 and 22 months. Biomarkers for oxidative damage to proteins and DNA also showed progressive oxidative damage to those macromolecules in cones during the course of RP. These data support the hypothesis that the death of rods results in decreased oxygen consumption and hyperoxia in the outer retina resulting in gradual cone cell death from oxidative damage. This hypothesis has important therapeutic implications and deserves rapid evaluation.
视网膜色素变性（RP）是一种常见的致盲原因，由许多不同基因中的大量不同突变引起。这些突变导致视杆光感受器细胞死亡，但视锥细胞为何死亡尚不清楚。在本研究中，我们通过对RP转基因猪模型中氧化损伤生物标志物进行免疫组织化学染色，来检验视锥细胞死于氧化损伤这一假说。蛋白质上丙烯醛和4-羟基壬烯醛加合物的存在是脂质过氧化发生的特异性指标，在两只10月龄几乎所有视杆细胞均已死亡的转基因猪的视锥细胞内节（IS）中，二者均有强烈的免疫荧光染色，而在两只10月龄对照猪视网膜中染色较弱。在所有视杆细胞和许多视锥细胞均已死亡的22月龄和24月龄转基因猪中，视锥轴突、一些细胞体以及内节均有强烈染色，表明在10至22个月间氧化损伤有所进展。蛋白质和DNA氧化损伤的生物标志物也显示，在RP病程中视锥细胞内的这些大分子存在进行性氧化损伤。这些数据支持以下假说：视杆细胞死亡导致视网膜外层氧消耗减少和高氧，从而导致视锥细胞因氧化损伤而逐渐死亡。这一假说具有重要的治疗意义，值得迅速评估。
