Singh Mahavir, Tyagi Suresh C
Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Med Hypotheses. 2017 Aug;105:17-21. doi: 10.1016/j.mehy.2017.06.012. Epub 2017 Jun 23.
Age-related macular degeneration (AMD) and pyroptosis cause irreversible vascular changes in the eyes leading to central vision loss in patients. It is the most common eye disease affecting millions of people aged 50years or older, and is slowly becoming a major health problem worldwide. The disease mainly affects macula lutea, an oval-shaped pigmented area surrounding fovea near the center of retina, a region responsible for visual acuity. It is fairly a complex disease as genetics of patients, environmental triggers as well as risk factors such as age, family history of CVDs, diabetes, gender, obesity, race, hyperopia, iris color, smoking, diabetes, exposure to sun light and pyroptosis have all been clubbed together as probable causes of macular degeneration. Among genes that are known to play a role include variant polymorphisms in the complement cascade components such as CFH, C2, C3, and CFB as potential genetic risk factors. So far, AMD disease hypothesized theories have not resulted into the anticipated impact towards the development of effective or preventive therapies in order to help alleviate patients' suffering because, as of today, it is still unclear what actually initiates or leads to this dreaded eye condition. Based upon our extensive work on the metabolism of homocysteine (Hcy) in various disease conditions we, therefore, are proposing a novel hypothesis for AMD pathogenesis as we strongly believe that Hcy and events such as pyroptosis make a greater contribution to the overall etiology of AMD disease in a target population of susceptible hosts by inciting and accelerating the inherent inflammatory changes in the retina of these patients (Fig. 2). In this context, we further state that Hcy and pyroptosis should be considered as legitimate and valuable markers of retinal dysfunction as they not only aid and abet in the development but also in the progression of AMD in older people as discussed in this paper. This discussion should open up new avenues in tackling inflammatory and pyroptosis centered pathways that are up-regulated or solely promoted by Hcy interaction within the ocular compartment of AMD susceptible hosts.
年龄相关性黄斑变性（AMD）和细胞焦亡会导致眼睛出现不可逆的血管变化，从而导致患者中心视力丧失。它是影响数百万50岁及以上人群的最常见眼病，并且正逐渐成为全球范围内的一个主要健康问题。该疾病主要影响黄斑，黄斑是视网膜中心附近围绕中央凹的椭圆形色素沉着区域，该区域负责视力。这是一种相当复杂的疾病，患者的遗传因素、环境诱因以及年龄、心血管疾病家族史、糖尿病、性别、肥胖、种族、远视、虹膜颜色、吸烟、糖尿病、阳光照射和细胞焦亡等风险因素都被认为是黄斑变性的可能病因。已知发挥作用的基因包括补体级联成分如CFH、C2、C3和CFB中的变异多态性，它们是潜在的遗传风险因素。到目前为止，AMD疾病的假说理论尚未对有效或预防性治疗的开发产生预期影响，以帮助减轻患者的痛苦，因为直到今天，仍然不清楚究竟是什么引发或导致了这种可怕的眼部疾病。基于我们在各种疾病状态下对同型半胱氨酸（Hcy）代谢的广泛研究，因此，我们提出了一种关于AMD发病机制的新假说，因为我们坚信Hcy和细胞焦亡等事件通过激发和加速这些患者视网膜中固有的炎症变化，对易感宿主目标人群中AMD疾病的整体病因学做出了更大贡献（图2）。在这种情况下，我们进一步指出，Hcy和细胞焦亡应被视为视网膜功能障碍的合理且有价值的标志物，因为正如本文所讨论的，它们不仅有助于AMD在老年人中的发展，而且有助于其进展。这一讨论应该为解决以炎症和细胞焦亡为中心的途径开辟新的途径，这些途径在AMD易感宿主的眼内隔室中因Hcy相互作用而上调或仅由其促进。
