氩激光视网膜光凝治疗增殖型糖尿病视网膜病变的疗效

对增殖性糖尿病视网膜病变(proliferative diabetic retinopathy,PDR)患者270例363眼氩激光视网膜光凝疗效进行分析。光凝后新生血管消退、未再玻璃体出血者占63.6%，其中视网膜新生血管与视盘新生血管、视网膜新生血管合并视盘新生血管间疗效差异均非常显著(P<0.01)；单纯新生血管与新生血管合并玻璃体出血行间疗效差异非常显著(P<0.01)。表明氩激光视网膜光凝治疗增殖性糖尿病视网膜病变的疗效与新生血管的存在部位及是否合并玻璃体出血有关。 （中华眼底病杂志，1995，11：227-228）     

氧诱导视网膜病变动物模型在视网膜新生血管治疗中的应用

氧诱导视网膜病变(oxygen-induced retinopathy,OIR)模型是研究视网膜新生血管常用的动物模型,多种治疗视网膜新生血管的研究,如与氧自由基相关药物、与血管内皮生长因子相关的药物等都使用了OIR模型.近年来干细胞治疗视网膜新生血管成为研究的热点,OIR模型又被广泛使用,并取得了满意结果.     

视网膜周边部新生血管的间接治疗

在镰状细胞贫血性视网膜增殖性病变(proliferation sickle cell retinopathy)、Eales病和滑石粉视网膜病变(talc retinopathy)等许多情况下,视网膜周边部可发生新生血管,如不治疗,可导致玻璃体出血和视网膜脱离。鉴于以往对新生血管丛(neovascular fronds)的营养血管用直接光凝或冰冻-解冰疗法封闭后并发症较多,作者根据在糖尿病     

血管生成促进因子在糖尿病视网膜病变新生血管形成中的作用

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病最常见和最严重的并发症之一.目前,DR的发病机制尚不明确,但近年来研究表明,血管生成促进因子与DR新生血管的发生、发展密切相关,是导致视网膜新生血管形成的主要致病因子.本文就血管生成促进因子在DR新生血管形成中的作用进行综述.     

玻璃体腔内注射Avastin治疗糖尿病视网膜病变的临床研究

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病(diabetes mellitus,DM)的严重并发症,是DM患者视力丧失的主要原因。黄斑水肿和视网膜新生血管是其两个主要原因。近年来的一种新兴疗法即血管内皮生长因子抑制剂avastin玻璃体腔注射治疗DR受到广泛的关注,为DM患者的视力保障提供了一个新型渠道。     

β肾上腺素能受体拮抗剂治疗眼部新生血管疾病的研究进展

眼部新生血管形成是糖尿病视网膜病变、早产儿视网膜病变、视网膜中央静脉阻塞和老年性黄斑变性等多种眼部疾病的病理学改变, 严重影响患者视力。β受体在结膜、角膜上皮细胞、角膜内皮细胞、眼外肌、小梁网、睫状肌、晶状体和视网膜中均有表达。β肾上腺素能受体拮抗剂与β受体结合, 通过抑制血管内皮生长因子(VEGF)、缺氧诱导因子-1、白细胞介素-6等促血管生成细胞因子, 降低巨噬细胞相关炎症反应, 增加抗血管生成因子表达来发挥抗血管生成作用。其在治疗角膜新生血管、脉络膜新生血管、早产儿视网膜病变时, 可显著减少新生血管面积, 延缓疾病进展, 联合应用抗VEGF药物可减少抗VEGF药物的给药频率。在有效的治疗浓度下, β肾上腺素能受体拮抗剂表现出良好的耐受性;且其较抗VEGF药物有更广泛的靶点, 为角膜、脉络膜和视网膜新生血管等眼部新生血管性疾病提供了新的治疗策略。     

VEGF在糖尿病视网膜病变发病机制中作用的研究新进展

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病最常见的微血管并发症之一,其基本病理改变是血-视网膜屏障(blood-retinal barrier,BRB)破坏、新生血管形成,后期新生血管膜收缩牵拉引起视网膜脱离。DR的发病机制十分复杂,至今尚未完全阐明。任何病理改变在本质上均是体内动态平衡的失调,新生血管的形成亦然,血管刺激因素增强和(或)抑制因素减少使两者平衡失调即所谓的"血管生成开关"形成。血管内皮生长因子(vascularendothelial growth factor,VEGF)是体内促新生血管形成的主要因子之一,近年来在DR的发病机制以及治疗的研究中广受关注。我们旨在阐述VEGF在DR发病机制中的作用。     

TNP470治疗高氧诱导幼鼠视网膜病变的作用

目的:探讨TNP470[O-(氯乙酰氨甲酰基)烟曲霉醇]治疗高氧诱导的早产儿视网膜病变的幼鼠模型(oxygen induced retinopathy,OIR)的作用.方法:选择鼠龄为7d的C57BL/6J幼鼠60只,分为正常对照组、高氧对照组、大、小剂量药物治疗组及实验对照组.随机取48只幼鼠置于浓度约为750mL/L的氧环境中连续生活5d,建立高氧诱导的早产儿视网膜病变动物模型.治疗组幼鼠取12只TNP470 30mg/kg SC为大剂量治疗组,另取12只鼠皮下注射TNP470 10mg/kg为小剂量治疗组,其余两组各12只小鼠SC相同体积的30mL/L酒精作为对照.每组随机取2只乳鼠4眼作视网膜铺片,观察视网膜血管变化.视网膜组织切片HE染色观察并计数突破视网膜内界膜的血管内皮细胞核数目,探讨TNP470对视网膜新生血管形成的抑制作用.结果:高氧环境对照组与正常环境对照组相比,视网膜有大量新生血管形成,结构及分布紊乱,说明高氧诱导的早产儿视网膜病变动物模型诱导成功;正常对照组与高氧环境对照组相比,药物治疗组与高氧对照组相比突破视网膜内界膜的血管内皮细胞核数目明显减少(P＜0.001).大、小剂量治疗组相比较差异明显(P＜0.01).结论:TNP470有抑制早产儿视网膜新生血管形成的作用.     

PTK787抑制早产儿视网膜病变大鼠模型新生血管的形成

目的探讨受体酪氨酸激酶亚群抑制剂PTK787对早产儿视网膜病变(retinopathy of prematurity,ROP)新生血管形成的抑制作用。方法建立波动氧(体积分数80%和10%氧浓度24h反复交替)诱导的SD大鼠ROP模型。67只新生SD大鼠随机设立对照组(22只)、模型组(22只)、治疗组(23只,腹腔注射PTK78750mg.kg-1);分别于第12天和第17天,每组随机抽取8只新生鼠,一侧眼球采用ADP酶组织化学法进行视网膜铺片,观察视网膜血管改变;另一侧眼球视网膜组织切片观察并计数突破视网膜内界膜的血管内皮细胞核数目。结果波动氧可成功诱导SD新生大鼠ROP模型,PTK787可抑制氧诱导新生鼠视网膜病变模型新生血管的形成。第12天和第17天时,模型组视网膜ADP酶组织化学铺片,均较对照组血管分布、密度改变明显;而治疗组视网膜铺片血管密度较模型组明显下降。第17天突破视网膜内界膜的血管内皮细胞核计数结果显示,给氧模型组31.360±4.543与正常对照组1.700±1.216比较,差异有显著统计学意义(t=-56.414,P<0.001)。治疗组6.800±2.107与模型组相比,血管内皮细胞核数显著减少(t=-43.869,P<0.001)。结论 PTK787可以抑制视网膜新生血管的形成,有望成为治疗ROP的有效途径。     

视网膜新生血管的药物治疗研究进展

全身或局部的病变可导致血—视网膜屏障破坏、血液微循环障碍和血管通透性改变,进一步引起视网膜缺氧,乃至水肿,随之视网膜组织对缺氧发生一系列代偿性反应,在各种细胞因子、细胞内外调控机制的共同作用下生成新生血管,目的是补偿缺血缺氧的视网膜。视网膜新生血管相关疾病包括糖尿病性视网膜病变、视网膜静脉周围炎、早产儿视网膜病变等。抑制新生血管生长是治疗这类疾病的关键。本文对抑制视网膜新生血管药物的研究进展作一综述。     

先天性视网膜血管变异的临床表现特征

目的:总结几种先天性视网膜血管变异的临床特征,以便与常见视网膜疾病的鉴别诊断。方法:对通过眼部检查诊断为先天性视网膜血管变异的11例16眼患者进行眼底彩色照相和荧光素眼底血管造影(fundus fluorescein angiography,FFA)检查。结果:患者11例16眼的血管变异明显位于视网膜后极部。先天性视网膜血管变异有4种类型:(1)先天性视网膜粗大血管1例1眼;(2)先天性视网膜血管迂曲6例11眼;其中先天性视网膜静脉迂曲3例6眼,先天性视网膜动静脉迂曲1例1眼,先天性视网膜小动静脉迂曲2例4眼;(3)先天性视盘血管袢3例3眼;(4)先天性视网膜血管异行1例1眼。并发视网膜出血有4例4眼。结论:先天性视网膜血管变异常可发生在视网膜动脉或静脉,可表现为单眼,多见于视网膜后极部,部分患者可诱发视网膜出血,有别于糖尿病视网膜病变或其他常见视网膜血管性疾病。     

Comparison of venous filling times and SLO findings at each quadrant region in diabetic retinopathy

Our purpose is to evaluate the correlation of retinal venous filling time (VFT), which reflects the peripheral retinal microcirculation in diabetic retinopathy, with fluorescein angiography (FAG) findings such as microaneurysm (MA), non-perfusion area (NP), neovascularization (NV) and relative retinal venous diameter (RRVD), and further, to evaluate the correlation between arteriovenous passage time (AVPT) and these factors. Partial F-test (multiple regression analysis) was performed on patients (32 eyes of diabetic retinopathy) who underwent video FAG, using scanning laser ophthalmoscope. In the four quadrants, VFT was compared with each MA, NP, and NV at each vascular arch at a distance of one disc diameter distant from the optic disc. VFT was significantly correlated to RRVD, NP, and NV at each quadrant (r > 0.7). However, AVPT was not significantly correlated to any of the factors studied. Delayed VFT was associated with the hemodynamic change of the peripheral retinal microcirculation at each quadrant in diabetic retinopathy. VFT can be used as an index to indicate the peripheral microcirculation of the retina.     

Expressions of survivin and vascular endothelial growth factor in a Murine model of proliferative retinopathy

AIM: To examine the expression of survivin and vascular endothelial growth factor(VEGF) during the development of retinal neovascularization (NV) in a mouse model. METHODS: A well-characterized murine model of retinal NV was used to study the expression of survivin and VEGF. NV of the retina was induced in mice by exposure to 75% O2 from postnatal day P7 to P12, followed by return to room air from P12 to P17. Expression of survivin and VEGF protein was analyzed by Immunohistochemistry. In addition, mouse model of proliferative retinopathy was analyzed by retinal fluorescein angiography and quantification analysis. RESULTS: The normal mice had both superfiekal and deep vascular layers that extended from the optic nerve to the periphery. In intraocular pressure(IOP) mice were characterized by represent a typical pattern of pathological retinal NV. There are less or little nuclei of new vessels vascular endothelial cell breaking through the inner retinal than in retinopathy of prematurity (ROP) mice, large clusters of blood vessels were adherent to the internal limiting membrane(ILM) (0.27±0.20 vs 23.38±1.027, t=9.454, P<0.001). During the angiogenic period from P13 to P17, survivin and VEGF protein expression increased in experimental retinas compared with control samples(2.56±0.46 vs 3.34±0.40, t=17.43, P<0.01: 2.18±0.75 vs 4.34±0.25, t=19.61, P<0.01). Protein levels of VEGF and survivn has significantly positive correlation (P<0.05, r=0.411). CONCLUSION: Correlation was made at the protein levels of survivin expression compared with that of VEGF in a murine model of retinal NV, which suggests a temporal role for survivin and VEGF in new vessel formation in response to hypoxic stimulation.     

Argon laser panretinal photocoagulation in ischemic central retinal vein occlusion

We conducted a prospective, planned study of argon laser panretinal photocoagulation (PRP) in ischemic central retinal vein occlusion (CRVO) over a 10-year period in 123 eyes. On comparing the lasered eyes versus the nonlasered eyes, there was no statistically significant difference between the two groups in the incidence of development of angle neovascularization (NV), neovascular glaucoma (NVG), retinal and/or optic disc NV, or vitreous hemorrhage, or in visual acuity. Our study, however, did show a statistically significant (P= 0.04) difference in the incidence of iris NV between the two groups, with iris NV less prevalent in the laser group than in the nonlaser group, butonly when the PRP was performed within 90 days after the onset of CRVO. The other parameter which showed a statistically significant difference between the two groups was the peripheral visual fields — the laser group suffered a significantly (P0.03) greater loss than the non-laser group. We discuss the implications of these findings in light of the natural history of ischemic CRVO and of ocular NV. Since the original rationale for advocating PRP in ischemic CRVO was the proven beneficial effect of PRP on ocular NV in proliferative diabetic retinopathy, we also discuss the disparities in the disease process between ischemic CRVO and proliferative diabetic retinopathy and in their responses to PRP.This investigation was supported by grant EY-1151 from the National Institutes of Health, and in part by unrestricted grants from Research to Prevent Blindness, Inc., and from the Alcon Research Institute     

Expressions of survivin and vascular endothelial growth factor in a Murine model of proliferative retinopathy

AIM: To examine the expression of survivin and vascular endothelial growth factor(VEGF) during the development of retinal neovascularization (NV) in a mouse model. METHODS: A well-characterized murine model of retinal NV was used to study the expression of survivin and VEGF. NV of the retina was induced in mice by exposure to 75% O2 from postnatal day P7 to P12, followed by return to room air from P12 to P17. Expression of survivin and VEGF protein was analyzed by Immunohistochemistry. In addition, mouse model of proliferative retinopathy was analyzed by retinal fluorescein angiography and quantification analysis. RESULTS: The normal mice had both superfiekal and deep vascular layers that extended from the optic nerve to the periphery. In intraocular pressure(IOP) mice were characterized by represent a typical pattern of pathological retinal NV. There are less or little nuclei of new vessels vascular endothelial cell breaking through the inner retinal than in retinopathy of prematurity (ROP) mice, large clusters of blood vessels were adherent to the internal limiting membrane(ILM) (0.27±0.20 vs 23.38±1.027, t=9.454, P<0.001). During the angiogenic period from P13 to P17, survivin and VEGF protein expression increased in experimental retinas compared with control samples(2.56±0.46 vs 3.34±0.40, t=17.43, P<0.01: 2.18±0.75 vs 4.34±0.25, t=19.61, P<0.01). Protein levels of VEGF and survivn has significantly positive correlation (P<0.05, r=0.411). CONCLUSION: Correlation was made at the protein levels of survivin expression compared with that of VEGF in a murine model of retinal NV, which suggests a temporal role for survivin and VEGF in new vessel formation in response to hypoxic stimulation.     

Suppression of retinal neovascularization by the iNOS inhibitor aminoguanidine in mice of oxygen-induced retinopathy

Background  Retinal neovascularization (NV) is a major cause of blindness associated with ischemic retinal disorders. Our study was focused on evaluating the inhibitory effect of aminoguanidine (AG), an inhibitor of inducible nitric oxide synthase (iNOS), on retinal NV in mice of oxygen-induced retinopathy (OIR). Methods  An OIR model was established with 7-day-old C57BL/6J mice. One day before and 1 and 3 days after being returned to the room air, the right eyes were injected intravitreally with bevacizumab, AG or bevacizumab+AG respectively. The left eyes were injected with normal saline (NS) as control. The mice were killed at postnatal day 17 (P17). The effects of AG or bevacizumab on iNOS or VEGF expressions were evaluated by RT-PCR and immunohistochemistry. Retinal NV was examined by fluorescein angiography, and was quantified histologically by CD34 immnunostaining at P17. Results  Compared with NS-treated eyes, retinal VEGF and iNOS mRNA expressions were significantly reduced in AG- and bevacizumab+AG-treated eyes; whereas in bevacizumab-treated eyes, retinal VEGF mRNA expression increased and iNOS mRNA expression remained unchanged. The above changes were confirmed by immunohistochemical study. The generalized decrease in both VEGF and iNOS distributions in mice retina treated with AG or bevacizumab+AG was demonstrated by immunohistochemistry. Retinal NV was significantly reduced in all three groups treated with bevacizumab, AG or bevacizumab+AG, when compared with NS-treated eyes. Conclusions  iNOS activation plays a pathological role in retinal NV in a mouse model of ischemic retinopathy. Administration of AG significantly suppressed retinal NV. Therefore, AG appears to be a novel and effective therapeutic approach for retinal NV. Ling Wang and Guo-Tong Xu are co-corresponding authors who contributed equally to this study.     

Postnatal growth retardation exacerbates acidosis-induced retinopathy in the neonatal rat

PURPOSE: We have previously described a metabolic acidosis-induced retinopathy in the neonatal rat, similar to retinopathy of prematurity (ROP). We also have reported exacerbation of oxygen-induced retinopathy by postnatal growth retardation, produced by raising newborn rats in 'expanded' litters. In the present study, we investigated the effect of postnatal growth retardation on the incidence and severity of acidosis-induced retinopathy. METHODS: 100 newborn Sprague-Dawley rats were randomly assigned to two expanded litters of 25 pups each and five standard control litters of 10 pups each. All rats were gavaged with 10 mM/kg NH(4)Cl twice daily from days two to seven. Following five days of recovery, retinal vasculature was assessed using ADPase staining, light microscopy, and computer-assisted image analysis. The presence of neovascularization (NV), severity of NV (clock hours), and vascularized retinal areas, were evaluated in a masked manner. RESULTS: NV occurred in 52% of rats in expanded litters versus 18% of rats in standard control litters (p = 0.005). Postnatal growth retardation of pups in expanded litters was confirmed by comparing total body weight of pups raised in expanded and standard control litters (10.8g vs 13.4g on day 8, p < 0.001; 20.8g vs 25.2g on day 13, p = 0.002). CONCLUSIONS: Postnatal growth retardation increases the incidence of acidosis-induced retinopathy in the neonatal rat. Our study provides further evidence that postnatal growth retardation is a risk factor for preretinal neovascularization in immature retinae and is consistent with the clinical observation that the smallest and sickest premature infants are more likely to suffer from ROP.     

玻璃体切除联合白内障手术治疗55例PDR疗效分析

目的:评价玻璃体切除联合晶状体超声乳化及人工晶状体植入术治疗增生性糖尿病视网膜病变(PDR)的疗效及并发症。方法:回顾性分析55例68眼伴有白内障的PDR患者行玻璃体切除联合晶状体超声乳化及人工晶状体植入术的临床资料,观察术后视力改善程度及术中、术后并发症。结果:术后随访3～24(平均8.5)mo。51眼(75%)术后视力维持或改善,17眼(25%)视力下降,其中无光感6眼(9%);术中并发症为医源性视网膜裂孔15眼(22%);术后并发症:前房炎性反应30眼(44%),玻璃体积血11眼(16%),复发性视网膜脱离3眼(4%),虹膜红变5眼(7%),新生血管性青光眼2眼(3%);31眼(46%)术后需要继续眼内光凝。结论:玻璃体切除联合晶状体超声乳化及人工晶状体植入术治疗PDR,可使大多数患者的视力改善,手术是安全的,手术成功的关键为选择合适的患者,影响术后视力的主要因素为视网膜病变程度。     

Molecular pathogenesis of retinal and choroidal vascular diseases

There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF antagonists a priority.