NLRP3 and autophagy in retinal ganglion cell inflammation in age-related macular degeneration: potential therapeutic implications

Retinal degenerative diseases were a large group of diseases characterized by the primary death of retinal ganglion cells (RGCs). Recent studies had shown an interaction between autophagy and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes, which may affect RGCs in retinal degenerative diseases. The NLRP3 inflammasome was a protein complex that, upon activation, produces caspase-1, mediating the apoptosis of retinal cells and promoting the occurrence and development of retinal degenerative diseases. Upregulated autophagy could inhibit NLRP3 inflammasome activation, while inhibited autophagy can promote NLRP3 inflammasome activation, which leaded to the accelerated emergence of drusen and lipofuscin deposition under the neurosensory retina. The activated NLRP3 inflammasome could further inhibit autophagy, thus forming a vicious cycle that accelerated the damage and death of RGCs. This review discussed the relationship between NLRP3 inflammasome and autophagy and its effects on RGCs in age-related macular degeneration, providing a new perspective and direction for the treatment of retinal diseases.     

印度西部近视儿童视网膜变性的病变程度及其决定性因素

目的:研究≥3.00D近视儿童视网膜变性的的发病率,类型和决定因素.方法:选取研究对象为2010/2011年期间在印度马哈拉施特拉邦一所眼科医院就诊的患者.询问并记录高度近视儿童家属成员的近视史,并统计人口信息.由验光师评估每位患者的视力和屈光状态.由眼科医生对患儿进行眼科检查,评估中央和周边视网膜变化.计算出中央及周边视网膜变性的百分比.评估视网膜改变与家族近视史性别、年龄、宗教以及近视程度的相关性.应用单因素和多因素分析.结果:共纳入≥3.00D近视儿童499位(847眼).检查发现150眼(17.7％,95％可信区间15.4 ～ 20.4)玻璃体视网膜退化性改变.黄斑变性、后巩膜葡萄肿及格子样变性比例分别为2.0％、4.6％和18％.眼轴大于24 mm是大于5.00D近视发生玻璃体视网膜退化性改变的显著危险因素(OR=3.88).视觉辅助的依从性为58.4％.499位患儿中8.8％视力低于6/60,他们可借助于低视力保健.结论:近1/5近视患者存在玻璃体视网膜变性.高度近视玻璃体视网膜变性较少有严重后果.建议应定期对近视眼进行详细的视网膜检查.     

一种稳定标记小鼠视网膜内两种不同类型神经节细胞的方法

目的 报道一种简单高效显示小鼠视网膜中两种不同类型神经节细胞的方法.方法 利用特殊标记物Brn3a和Melanopsin,通过视网膜铺片免疫荧光双标染色结合激光共聚焦显微镜,分别标记小鼠视网膜中普通视网膜神经节细胞和内在光敏视网膜神经节细胞.结果 免疫荧光染色结果表明,内在光敏视网膜神经节细胞与普通视网膜神经节细胞均位于视网膜节细胞层,相间互补分布.内在光敏视网膜神经节细胞数量较少,为普通视网膜神经节细胞的1％ ～2％,其轴突朝向视神经盘方向汇集,树突野较大,伸向内网层.结论 免疫荧光双标染色是小鼠视网膜内两种不同类型视网膜神经节细胞简单易行、稳定高效的标记方法.     

Phenotypic findings in C1QTNF5 retinopathy (late‐onset retinal degeneration)

Purpose: To describe the ocular and electrophysiological phenotype of four patients with late‐onset retinal degeneration (LORD). Methods: Clinical examination, fundus and anterior segment photography, fundus autofluorescence imaging and spectral domain optical coherence tomography (SD‐OCT) were performed. Three patients underwent pattern and full‐field electroretinography (ERG). Patient DNA was screened for the c.686C>G, p.Ser163Arg mutation in C1QTNF5. Results: All affected individuals had a family history suggestive of autosomal dominant inheritance with full penetrance. Molecular analysis identified a heterozygous c.686C>G, p.Ser163Arg mutation in C1QTNF5 in DNA from all four affected probands. All four patients presented in their 50s with nyctalopia and developed central visual loss in their 60s. Peripupillary iris atrophy and long anterior zonular insertions were present in three of four patients. Dilated fundus examination revealed scalloped areas of retinal pigment epithelium (RPE) atrophy in the mid‐periphery and widespread atrophy in the posterior pole. Full‐field ERGs were consistent with rod‐cone dystrophy with pattern ERG evidence of severe macular involvement. SD‐OCT revealed widespread loss of the photoreceptors with absence of the inner/outer segment junction line and concurrent thinning of the outer nuclear layer. Diffuse choroidal thinning, mainly affecting the inner choroid with loss of the choriocapillaris, was observed. Conclusion: C1QTNF5 retinopathy is an autosomal dominant LORD resulting in a complex ocular phenotype involving the RPE and ciliary epithelium. SD‐OCT findings revealed widespread photoreceptor loss and diffuse choroidal thinning.     

青光眼视网膜神经节细胞凋亡的实验研究

目的 研究兔的实验性青光眼视网膜神经节细胞的死亡是否有凋亡参与。方法 前房注入固定的红细胞悬液使免眼压升高,分别在术后７,１４,２１,２８天处死动物,取视网膜组织,ＴＵＮＥＬ标记染色,电镜观察。结果 电镜下可见视网膜神经节细胞死亡特征为典型的凋亡早期特征－核浓染。免疫组ＴＵＮＥＬ法实验组发现神经节细胞凋亡,而正常对照组没有发现。结论 实验性青光眼的视网膜神经节细胞死亡有凋亡参与。这为通过调探凋亡而治疗青光眼的视网膜视神经损伤提供可能。     

视网膜血管瘤样增生和湿性年龄相关性黄斑病变的鉴别

视网膜血管瘤样增生(retinal angiomatous proliferation,RAP)是湿性年龄相关性黄斑变性(age-related macular degeneration,AMD)的一种特殊类型,临床一般分三期,晚期有新生血管形成,但与起源于脉络膜的新生血管不同,多数学者认为RAP的新生血管起源于视网膜深层毛细血管网。目前对RAP和湿性AMD两者到底是同一种疾病的不同亚型还是独立的两种疾病还存在争议,由于两者的病程、预后及治疗存在差异,因此临床鉴别诊断十分重要。近年来,随着吲哚菁绿血管造影(indocyanine green angiography,ICGA)技术和新一代光学相干断层扫描(optical coherence tomography,OCT)技术的应用,对RAP和湿性AMD的鉴别取得了显著进步。本文就两者的临床表现、自然病程、治疗方法及预后等方面做一综述。     

The emerging role of proteases in retinal ganglion cell death

Retinal ganglion cell (RGC) death is an important issue in Primary Open Angle-Glaucoma (POAG) in terms of both vision loss and health care costs. Yet, the pathophysiology underlying RGC death in glaucoma is unclear. A growing body of evidence indicates that proteases that modulate the extracellular matrix (ECM) milieu in the retina, either directly or indirectly, play an important role in dictating the fate of RGCs. Recent evidence indicates that proteases, in addition to ECM-remodeling, have broader functional roles in glutamate receptor processing and predisposing RGCs to secondary damage. This review is focused on discussing the role of two groups of proteases, the matrix metalloproteinases (MMPs) and the plasminogen activators (PAs), in RGC death. In a long-run, a better understanding of the mechanisms involved in the regulation of proteases may lead to the development of adjunctive treatment options to attenuate RGC death and improve vision loss in glaucoma.     

自噬在视网膜和眼部疾病中的研究进展

自噬维持细胞内成分降解和再循环的稳态,是一种关键的细胞质量控制机制。在应激反应中,自噬促进细胞成分的降解,以提供细胞代谢所需的营养物质和能量。视网膜是眼睛中转导和处理视觉信息的光敏组织,对物质和能量需求极高,基础水平的自噬对维持视网膜细胞的稳态和视觉系统的正常功能至关重要。本文总结了自噬途径参与青光眼、年龄相关性黄斑变性、糖尿病视网膜病变、视网膜营养不良和视网膜脱离等眼科疾病的最新研究,为未来通过调控自噬治疗眼部疾病提供理论依据。     

Hereditary retinal degeneration in the Rhode Island Red chicken. I. Histology and ERG

Hereditary blindness in Rhode Island Red chickens was analyzed at various post-hatching stages by light microscopy and electrophysiological recordings. At the time of hatching the retina of affected chicks appeared morphologically normal and identical to that of control, non-affected chicks. Whereas the electroretinographic (ERG) response to light stimulus in normal chicks was near the adult level at the time of hatching, no ERG either under light- or dark-adapted conditions was measurable in affected chicks at any stage examined. Photoreceptor cells of affected animals were seen to undergo degenerative changes after about one week post-hatching. Decrease in number of outer segments, spaces between inner segments and large spaces in the outer nuclear layer were apparent by Day 10. By Day 21, most of the photoreceptor inner segments appeared swollen, and the decrease in number of outer segments and photoreceptor nuclei was noteworthy. By the end of the second month no outer segments were seen and the majority of identifiable inner segments were from cones, a larger proportion than normally present being double cones. By six months, very few photoreceptor inner segments and nuclei remained; most inner segments were deformed and diminutive but usually contained a clearstaining oil droplet characteristic of the principal member of the double cone. In all stages after one week of age, pycnotic nuclei and thinning of inner retinal layers accompanied photoreceptor degeneration. In all specimens examined, degeneration of retinal cells was more pronounced in the superior central retina than in the periphery. Pathological changes were frequently also noted in the pigment epithelium overlying degenerating retina. Because the chick retina is well developed at birth, contains a fovea and a significant cone population and because cones (particularly one specific type) survive rods, we believe that this congenitally-blind chicken may be a useful model for studies on human hereditary retinal degenerations.     

遗传性视网膜谱性视细胞凋亡与视网膜诱生型一氧化氮合酶活性的时程变化

目的 研究遗传性视网膜变性视细胞凋亡与诱生型一氧化氮合酶活性之间的关系。方法 对生后不同鼠龄RCS大鼠和Wistar大鼠的视网膜进行凋亡细胞的TUNEL检测、计算机自动图像分析及诱生型一氧化氮合酶活性的测定。结果 RCS大鼠视网膜视细胞自生后第25天出现凋亡,第30-35天达高峰;视细胞凋亡初期,即生后第25天,视网膜诱生型一氧化氮合酶活性达高峰。结论 在遗传性视网膜变性的视网膜。诱生型一氧化合酶激活可能在视细胞凋亡中起诱导作用。     

Muller细胞对青光眼视网膜神经节细胞影响的研究进展

视网膜神经节细胞（RGCs）的过度凋亡是青光眼病理改变的基础。Mller细胞作为视网膜的主要神经胶质细胞,对于维持神经元的完整性、代谢、内环境稳态以及信号转导等均具有重要的作用。随着对Mller细胞研究的逐渐深入,发现Mller细胞不仅参与了青光眼性RGCs的凋亡机制,而且还参与了RGCs的代偿性保护机制。那么Mller细胞是如何对RGCs起作用,它又是通过什么机制参与青光眼引起的RGCs凋亡以及代偿性保护作用呢？就这些问题的最新研究进展进行综述。     

Caspase inhibitors protect against NMDA-mediated retinal ganglion cell death

Background: Apoptosis is a major mechanism of cell death in glutamate‐induced excitotoxicity and caspases as the executors of apoptosis play an important role in the development of various central nervous system and eye diseases. We studied the involvement of certain caspases in excitotoxic retinal ganglion cell death, which was experimentally induced in Brown Norway Rats by application of the glutamate receptor agonist N‐methyl‐D‐aspartate (NMDA). Methods: Animals were injected intravitreally with one of six caspase inhibitors (against caspases 1, 3, 4, 6, 8 and 9). Seven hours later, NMDA or phosphate‐buffered saline as a control was injected intravitreally into the respective eyes. The neuroprotective potential against NMDA toxicity was assessed by retinal ganglion cell quantification. Additionally, wholemount TUNEL was performed. Results: Statistical analysis revealed significant neuroprotective effects for the inhibitors of caspases 3, 6, 8 and 9, but not for those of caspases 1 and 4. The inhibitors of caspases 6 and 9 showed greater neuroprotective potential than those of caspases 3 and 8, although cell death was not entirely averted in any case. Results of ganglion cell counts were confirmed for the most pronounced treatment groups using wholemount TUNEL. Conclusion: Excitotoxic retinal ganglion cell death after NMDA injection is mediated mainly through apoptosis, whereby extrinsic as well as intrinsic pathways of caspase activation play a role.     

电子烟对小鼠视网膜组织及超微结构影响的研究

目的:研究电子烟对小鼠视网膜组织及超微结构的影响以及可能的相关机制。方法:将18只8周龄雄性c57BL小鼠随机分为对照组(6只),0mg尼古丁组(6只)和12mg尼古丁组(6只),分别用HE染色观察视网膜各层结构的改变,在透射电子显微镜下观察视网膜色素上皮(RPE)细胞超微结构的改变,通过免疫荧光染色观察视网膜中Tuj1、8-OHdG的表达情况。结果:与对照组相比,实验组(0mg和12mg尼古丁组)视网膜全层、视神经纤维层和内丛状层厚度均显著减少(P<0.01),但实验组间均无明显差异(P>0.05)。RPE细胞顶部仅见零星微绒毛,残存微绒毛长度变短。实验组中节细胞层、视神经纤维层和内丛状层可观察到Tuj1表达减少,但是神经节细胞数目无显著变化(P>0.05)。0mg和12mg尼古丁组中节细胞层、内核层内观察到8-OHdG表达增加。结论:电子烟可对小鼠视网膜造成损伤,其损伤可能是由氧化应激反应造成的。     

氧化应激诱导视网膜神经节细胞凋亡的研究进展

视网膜神经节细胞(retinal ganglion cells,RGCs)凋亡是青光眼、糖尿病视网膜病变、视神经炎等多种疾病过程中的一个重要环节。在这些疾病过程中,氧化应激参与诱导RGCs的凋亡。近年的实验研究发现抗氧化应激药物对RGCs有良好的保护作用。我们将近年来氧化应激诱导RGCs凋亡以及相关抗氧化应激药物的研究进展做一综述。     

Autosomal dominant juvenile vitreoretinal degeneration and retinal detachment

To study the inheritance and clinical picture of a new form of vitreoretinal dystrophy I examined 18 family members of a family with six generations. Seven patients, three male and four female, in three consecutive generations were observed to be affected indicating autosomal dominant inheritance. The disease was characterized by juvenile degeneration of the vitreous with detachment of the vitreous body and some floating vitreous opacities, cystoid degeneration of the peripheral retina with whitish glistening stippled areas of superficial retinal degeneration, spotty hyperpigmentation, patches of retinal atrophy with pigmentations, occasional atrophic retinal holes, and in four family members at the age of 4 to 12 years, unilateral or bilateral retinal detachment with breaks in the peripheral retina. Most patients had hyperopia with or without astigmatism. In eyes without detached retina, the disease did not show any marked progression, the lens was clear, the posterior fundus and the retinal and choroidal vessels were normal, and the visual acuity, visual fields, dark adaptation, colour vision, electroretinograms, and visually evoked response findings were normal.     

Imaging retinal mosaics in the living eye

Adaptive optics imaging of cone photoreceptors has provided unique insight into the structure and function of the human visual system and has become an important tool for both basic scientists and clinicians. Recent advances in adaptive optics retinal imaging instrumentation and methodology have allowed us to expand beyond cone imaging. Multi-wavelength and fluorescence imaging methods with adaptive optics have allowed multiple retinal cell types to be imaged simultaneously. These new methods have recently revealed rod photoreceptors, retinal pigment epithelium (RPE) cells, and the smallest retinal blood vessels. Fluorescence imaging coupled with adaptive optics has been used to examine ganglion cells in living primates. Two-photon imaging combined with adaptive optics can evaluate photoreceptor function non-invasively in the living primate retina.     

Age-dependent rat retinal ganglion cell susceptibility to apoptotic stimuli: implications for glaucoma

Background: This paper seeks to investigate differences between the neonatal and adult retinal ganglion cell populations to apoptotic death stimuli. Design and Samples: In vitro and ex vivo paradigms involving P6 and P60 Sprague–Dawley rat retinal explants and retinal ganglion cells were employed. Methods: Postnatal day 6 (P6) and 60 (P60) Sprague–Dawley retinal ganglion cells and retinal explants were either serum starved or subjected to excitotoxicity using calcium ionophore A23187. Main Outcome Measures: Apoptosis was detected in both models using terminal dUTP nick end labelling. Expression of Apaf‐1, active caspases‐3 and 9 in P6 and P60 retinas, and in the ganglion cell layer was examined using Western blotting. Results: In both the dissociated retinal ganglion cell and retinal explant models, P60 retinal ganglion cells were significantly less susceptible to excitoxicity and serum starvation than their P6 counterparts. Western blotting indicated that active caspase‐3 and Apaf‐1 are downregulated in the Sprague–Dawley rat retina at P60 compared with P6 Conclusions: We demonstrate that neonatal Sprague–Dawley retinal ganglion cells are more susceptible to glaucoma‐related death stimuli than their adult counterparts in dissociated retinal ganglion cells and axotomized retinal explant models. It is apparent that these different retinal ganglion cell populations are inherently designed to react differently to death stimuli. Thus caution should be exercised when noting the high susceptibility of neonatal retinal ganglion cells to glaucomatous death stimuli.