后发性白内障的发病机制和药物防治的研究现状及前景

后发性白内障是现代白内障术后最常见的并发症。术后晶状体囊残留的晶状体上皮细胞的增殖、迁移、纤维化生是形成后发性白内障的主要原因。目前防治后发障的研究主要集中在药物除去或破坏残留晶状体上皮细胞。实验研究许多细胞毒药以及抑制晶状体上皮细胞生长和纤维化药物可以预防后发障,但目前临床上还没安全、有效的防治白内障方法。     

Posterior capsule opacification

Posterior capsule opacification (PCO) is the most common complication following primary cataract surgery. Advances in intraocular lens (IOL) designs that have reduced the amount of PCO following surgery have been made. The understanding of how the IOL design effects PCO has also advanced. Lenses that provide a mechanical barrier between it and the posterior lens capsule seem to inhibit PCO to a greater degree. Intracapsular rings are now being explored to test and enhance this barrier effect. Major advances in the elimination of lens epithelial cells at the time of surgery especially by pharmacologic means have also been made. An immunotoxin specific for human lens epithelial cells shows promise and is under latter phase clinical development.     

Posterior capsule opacification and anterior capsule opacification

Posterior capsule opacification (PCO) is still the most frequent complication of cataract surgery. A variety of studies has led to a better understanding of the pathogenesis of PCO, and strategies of molecular biology have produced new therapeutic options, such as immunological techniques or gene therapeutic approaches. Surgical strategies and intra-ocular lens-dependent factors also are capable to reduce the rate of PCO. In-the-bag implantation of intra-ocular lenses with a sharp optic edge seems to be effective in inhibiting equatorial lens epithelial cell migration to the center of the posterior capsule. Several PCO documentation systems have been developed that will lead to more exact and better comparable recording of PCO rates. In the year 2000, PCO or secondary cataract is still the most frequent complication after extracapsular cataract surgery. In a 1998 meta-analysis, PCO rates of 11.8% 1 year after extracapsular cataract surgery with intraocular lens implantation, 20.7% after 3 years, and 28.4 % after 5 years have been reported. For the United States, it has been estimated that the overall expenses for treatment of PCO are only exceeded by the costs for cataract treatment itself. In the past decade, a lot of experimental and clinical studies have been performed on this topic. They have led to 1) to a better understanding of the pathogenesis of the development of anterior and posterior capsule opacification; 2) more objective and better comparable systems of documentation and analysis of PCO; and a number of 3) surgical and 4) pharmaceutical strategies to prevent PCO.     

靶向治疗后囊混浊的研究进展

后囊混浊是白内障手术的常见并发症。残留晶状体上皮细胞在后囊的增殖、移行、纤维化生是后囊混浊形成的重要因素。用于防治后囊混浊的许多约物如道诺霉素、丝裂霉素等，因眼内的毒副作用而受到限制。靶向治疗的特异性、针对性为解决这一问题带来了希塑。综述了靶向治疗后囊混浊的研究现状及对未来的研究展望。     

体外模拟牛眼晶状体后囊膜混浊及普拉洛芬眼液对其细胞融合影响的实验研究

目的探讨晶状体后囊膜上晶状体上皮细胞的增生分化规律和普拉洛芬滴眼液对晶状体后囊膜混浊（PCO）的抑制作用.方法将牛后囊膜晶状体上皮细胞面朝上平铺于25 ml培养瓶底部,分别加入含0%、10%、20%胎牛血清的DMEM培养液培养1～5周,计数后囊膜晶状体上皮细胞覆盖率,并用Giemsa染色和扫描电镜观察其形态.同时用相当于普拉洛芬滴眼液滴眼后4 h在房水中的浓度（0.23 mg/L）作用于组织培养模型,与对照组比较,观察其对后囊膜晶状体上皮细胞融合时间的影响.结果赤道部的晶状体上皮细胞向晶状体后囊膜增生、迁徙,晶状体后囊膜形成明显的混浊和皱缩;后囊膜晶状体上皮细胞融合天数随血清浓度的升高而缩短;浓度为0.23 mg/L的普拉洛芬对后囊膜晶状体上皮细胞的融合有明显抑制作用.讨论体外模拟PCO的组织培养是研究后发性白内障的有效方法.普拉洛芬是一种安全、有效降低PCO发生率的药物,可作为白内障术后的常规用药.     

乙二胺四乙酸二钠对晶状体上皮细胞清除作用的实验研究

目的:探讨乙二胺四乙酸二钠(EDTA)对晶状体囊膜上皮细胞的清除效果。方法:收集白内障超声乳化囊外摘除术中环形撕取的晶状体前囊膜32例,将其随机分为4组,分别用5mmol/L,10mmol/L,20mmol/L EDTA及生理盐水进行前囊膜消化处理,观察晶状体上皮细胞的清除情况。结果:经过20mmol/L EDTA溶液处理的晶状体前囊膜,上皮细胞可以完全脱落,经过5mmol/L,10mmol/L EDTA溶液处理的晶状体前囊膜,上皮细胞部分脱落,生理盐水对照组仅见少量晶状体上皮细胞脱落。结论:EDTA可以清除晶状体囊膜的上皮细胞,并随浓度增加效果增强,该结果可为临床应用EDTA清除晶状体上皮细胞以防治后发性白内障(posterior capsular opacification,PCO)的发生提供实验基础和理论依据。     

Inhibitory effects of salmosin,a disintegrin,on posterior capsular opacification in vitro and in vivo

The proliferation, migration and transdifferentiation of the remaining lens epithelial cells (LECs) after cataract surgery are a major cause of posterior capsular opacification (PCO). It has previously been reported that salmosin, a novel disintegrin, significantly inhibits solid tumor growth in mice by perturbation of tumor-specific angiogenesis via blocking alpha v beta 3 integrin expressed on vascular endothelial cells. In this study, the inhibitory function of salmosin in PCO was investigated and was found that salmosin inhibits the attachment of bovine LECs and rabbit lens cells (N/N1003A) to extracellular matrix-coated plates. The anti-adhesive activity of salmosin was approximately 1000 times higher than that of synthetic Arg-Gly-Asp peptide. In addition, the cell proliferation and migration of bovine LECs and N/N1003A were strongly inhibited by salmosin, whereas the proliferation of corneal endothelial cells was less affected. LEC migration and proliferation were also decreased by salmosin treatment in rabbit eyes without any toxic effect in the cornea, iris and retina. In this study, salmosin was shown to specifically inhibit LEC migration and proliferation in an animal model. Therefore, the authors suggest that further investigation may show salmosin to be a good candidate for inhibiting PCO development.     

Lens epithelial inhibition by PMMA optic: implications for lens design

It has been a clinical impression that posterior chamber lens implants in some way inhibit opacification of the posterior lens capsule after extracapsular cataract extraction. The mechanism of this inhibition is unclear; it may be related to mechanical contact or blockage of migration of lens epithelial cells, or possibly to the leeching of toxic factors from the lens itself. A better understanding of the exact mechanism of opacification inhibition may have important clinical implications for intraocular lens design. For example, some lens designs that facilitate Nd:YAG capsulotomy by physically separating the posterior chamber lens and the posterior capsule may result in less inhibition and in fact more opacification of posterior capsules. We performed in vitro tissue culture studies of the effect of the polymethylmethacrylate (PMMA) optic of a planoconvex intraocular lens on cultured rabbit lens epithelium. These studies demonstrated both inhibition of lens epithelial migration beneath the PMMA optic (plano side down) as well as metaplasia and necrosis of lens cells growing directly beneath the optic. The clinical implications of these studies for intraocular lens design are discussed.     

In vitro model for the study of human posterior capsule opacification

PURPOSE: To develop and evaluate a model for the organ culture of human lens capsules that reduces problems inherent in preexisting models for the study of in vitro posterior capsule opacification (PCO). METHODS: Human lenses (N = 110) were isolated from donor eyes and supported externally within a lens holder system by medical-grade cyanoacrylate glue, allowing visualization of the entire capsular bag. After capsulorhexis and lens extraction were performed, the capsule specimens were maintained at physiological conditions for up to 4 weeks. The area of lens epithelial cell (LEC) coverage over the posterior capsule surface was determined objectively on a daily basis using a graticule. Lens epithelial cell behavior was correlated with clinical data and other in vitro PCO models. RESULTS: Cyanoacrylate glue did not appear to be toxic to LECs at the concentration used. The amount of viable epithelium after nuclear extraction was dependent on the age and postmortem time of the specimen. Viable LEC cultures were obtained from eyes up to 9 days postmortem. The time from death to culture or from enucleation to culture did not influence LEC viability if it was fewer than 5 days. The LEC proliferation rates and confluence times were age dependent and correlated closely between pairs of eyes. CONCLUSIONS: Results show that the lens holder model is a more physiological method for supporting the capsule and is a robust, reproducible system for the study of LEC migration and proliferation. It allows visualization within the entire capsular bag. Intraocular lenses can be implanted in this system in a way that more closely resembles the in vivo scenario. This model can be used to evaluate therapeutic measures to prevent PCO.     

Modification of the surface properties of a lens material to influence posterior capsular opacification

PURPOSE: To study the effect of surface properties of materials on cellular behaviour and the formation of posterior capsular opacification (PCO). METHODS: Polymethylmethacrylate, silicone and a hydrophobic acrylic were plasma treated and used in tissue culture. The changes in surface properties were quantified by dynamic contact angle measurements. Bovine lens epithelial cells (BLECs) were seeded onto these materials and cultured for 1 month. Serial photographs were taken. The cells were then fixed and stained to facilitate counting. RESULTS: Plasma treatment significantly increased the hydrophilicity of surfaces. BLECs grew on all surfaces but significantly more cells adhered to the treated than the untreated surfaces. On the untreated surfaces the BLECs had a fibroblastic morphology whereas on the treated surfaces the cells maintained their epithelial morphology. CONCLUSIONS: Posterior capsular opacification is a form of wound healing and the behaviour of lens epithelial cells is central to its progression. Emphasis has been on the elimination of residual lens epithelial cells to combat PCO. This study demonstrated that the phenotype of BLECs was influenced by the surface properties of the intraocular lens materials. Gas plasma treatment of the materials increased their hydrophilicity and allowed the adhered BLECs to maintain their normal epithelial morphology. We believe that controlled growth of lens epithelial cells may reduce the incidence of PCO.     

Effect of intraocular lens design on posterior capsule opacification: an in-vitro model

BACKGROUND: The development of posterior capsule opacification (PCO) is one of the commonest complications of modern cataract surgery. The various designs of intraocular lenses (IOL) seem to exert a barrier effect on the proliferation and migration of lens epithelial cells and the following development of PCO. METHODS: We set up a cell culture model (advanced 3D capsular bag model) and investigated six differently designed IOL made of different materials as to their effect on cell proliferation. Proliferation and migration of the cells were analysed and documented over a period of 28 days. A cell viability test using the LIVE/DEAD kit (Molecular Probes) was carried out at the end of the investigation. RESULTS: In all tests, lens epithelial cells adhered to and migrated onto the capsular bag. During the culture period, lens epithelial cells migrated only to the optical rim of two of the implanted IOL. On the other four, lens epithelial cells migrated further and covered the whole optical area of the IOL. CONCLUSIONS: Certain lens designs seem to have a reducing effect on the development of PCO. Our advanced in vitro capsular bag model is a suitable cell culture model for the investigation of the reducing effect of various IOL on the development of PCO.     

结缔组织生长因子与后发性白内障的研究进展

后发性白内障(又称后囊膜混浊)已成为白内障术后视力再度下降,影响术后远期视力恢复的突出问题,主要是由于残留的晶状体上皮细胞向后囊膜移行、增殖形成。结缔组织生长因子(connective tissue growth factor,CTGF)是近年来倍受关注的促纤维化细胞因子。本文对近年来CTGF与后发性白内障关系的研究进展综述如下。     

Posterior capsule opacification: What's in the bag?

Cataract, a clouding of the lens, is the most common cause of blindness in the world. It has a marked impact on the wellbeing and productivity of individuals and has a major economic impact on healthcare providers. The only means of treating cataract is by surgical intervention. A modern cataract operation generates a capsular bag, which comprises a proportion of the anterior capsule and the entire posterior capsule. The bag remains in situ, partitions the aqueous and vitreous humours, and in the majority of cases, houses an intraocular lens (IOL). The production of a capsular bag following surgery permits a free passage of light along the visual axis through the transparent intraocular lens and thin acellular posterior capsule. Lens epithelial cells, however, remain attached to the anterior capsule, and in response to surgical trauma initiate a wound-healing response that ultimately leads to light scatter and a reduction in visual quality known as posterior capsule opacification (PCO). There are two commonly-described forms of PCO: fibrotic and regenerative. Fibrotic PCO follows classically defined fibrotic processes, namely hyperproliferation, matrix contraction, matrix deposition and epithelial cell trans-differentiation to a myofibroblast phenotype. Regenerative PCO is defined by lens fibre cell differentiation events that give rise to Soemmerring's ring and Elschnig's pearls and becomes evident at a later stage than the fibrotic form. Both fibrotic and regenerative forms of PCO contribute to a reduction in visual quality in patients. This review will highlight the wealth of tools available for PCO research, provide insight into our current knowledge of PCO and discuss putative management of PCO from IOL design to pharmacological interventions.     

囊袋阻滞综合征患者囊袋内积聚液体及后发性白内障囊膜的蛋白质组成分析

目的　鉴定白内障术后囊袋阻滞综合征（capsular block syndrome,CBS）患者囊袋内积聚液体以及后发性白内障囊膜的蛋白质组成。方法　选取我院就诊的5例白内障超声乳化吸出联合人工晶状体植入术后CBS患者,继发青光眼且合并后发性白内障,吸出人工晶状体和后囊之间积聚的液体,撕除混浊的后发性白内障囊膜,用强裂解液提取蛋白质,进行液相色谱串联质谱鉴定分析,确定蛋白质组成,并根据Mascot搜索数据结果估算各成分的相对含量。所得蛋白质组成数据与同龄白内障患者晶状体皮质和晶状体上皮细胞的蛋白质主要组成进行比较及分析。结果　本研究中CBS患者人工晶状体和后囊之间积聚的液体和后发性白内障囊膜蛋白质组成中,含量较高（前10种）有细胞骨架类蛋白:晶纤蛋白、肌动蛋白、波形蛋白、锚蛋白2;晶状体蛋白:αA-晶状体蛋白、βB1-晶状体蛋白、αB-晶状体蛋白;葡萄糖代谢相关蛋白:三磷酸甘油醛脱氢酶、促进性葡萄糖转运蛋白;热休克蛋白A5。晶状体上皮细胞含量丰富的蛋白质（前15位）包含上述成分中的αA-晶状体蛋白、αB-晶状体蛋白、波形蛋白、肌动蛋白以及三磷酸甘油醛脱氢酶;而晶状体皮质检测到的含量较高的蛋白主要是各种晶状体蛋白,包含CBS患者囊袋内积液和后发性白内障囊膜组成中的βB1-晶状体蛋白、αA-晶状体蛋白、αB-晶状体蛋白。结论　CBS积聚的液体和后发性白内障囊膜主要蛋白质组成与晶状体上皮细胞更加相似,它们可能参与CBS囊袋内液体的积聚以及此种后发性白内障的形成。     

Comparison of design of intraocular lens versus the material for PCO prevention

AIM: To evaluate the influence of different intraocular lens(IOL) designs made of PMMA on posterior capsular opacification(PCO) and compare with foldable designs. METHODS: Phacoemulsification and IOL implantation was done in one eye of 24 New Zealand White rabbits, with IOL of two different designs (Square edged or round edge) and two different materials(PMMA or HEMA). After three months, the animals were sacrificed and enucleated. Evaluation of PCO included posterior view, migration of anterior capsular epithelial cells to the posterior capsule following epithelial-mesenchymal transition were assessed by staining the histological sections of posterior capsule by hematoxylin-eosin(HE) and Periodic acid- Schiff (PAS). The IOLs were extracted and stained with HE to evaluate the presence of adherent cells on the lens surface. RESULTS: PCO was highest with round edged rigid lens. There was no significant difference in the PCO between the square edged PMMA and square edged foldable lens. CONCLUSION: It is the design of the IOL not the material that offers protection on PCO formation.     

晶体上皮细胞在体外的分化规律及血清和眼组织对其增殖的影响

目的从细胞培养水平探讨后囊混浊形成机理和术后血－房水屏障破坏、晶体皮质残留等对其的影响。方法用考马斯亮蓝（ＣｏｏｍａｓｓｉｅＢＢ）染色、倒置显微镜和电镜观察培养的牛晶体上皮细胞（ｂｏｖｉｎｅｌｅｎｓｅｐｉｔｈｅｌｉａｌｃｅｌｓ，ＢＬＥＣ）的增殖和分化规律，用Ｇｉｅｍｓａ染色比色法观察胎牛血清、房水、晶体皮质等对ＢＬＥＣ增殖的影响。结果在体外培养条件下ＢＬＥＣ可在第１～７代内分化为晶体纤维细胞，表现为细胞体积增大，形状渐趋长条形和梭形，细胞骨架逐渐增多；胎牛血清呈浓度依赖性促进ＢＬＥＣ增殖（Ｐ＜０．０５）；高浓度房水（占培养液１／３）抑制ＢＬＥＣ增殖（Ｐ＜０．０１），晶体皮质、晶体核、玻璃体均促进ＢＬＥＣ增殖（Ｐ＜０．０１）。结论晶体上皮细胞的分化在后囊混浊形成中起重要作用；术后血－房水屏障破坏、晶体皮质残留和玻璃体脱出可通过刺激晶体上皮细胞增殖促进后囊混浊形成。     

改良大鼠后囊膜混浊模型的建立及晶状体上皮细胞的变化

目的:改良法建立大鼠后发性白内障动物模型并观察LEC在PCO过程中的动态变化。方法:SD大鼠50只在连续环形撕囊、水分离后行晶状体囊外摘除术(ECLE),娩核后使用无菌空气恢复前房。分别于术后0,3,7,14及28d对术眼进行裂隙灯检查并处死动物,摘除眼球行光镜观察,免疫组化检测LEC的α-SMA表达。结果:100%术眼后囊膜存在,84%的鼠眼可用于检测。术后0h于前囊下和赤道部的内表面观察到LEC。PCO在术后3d出现,出现囊膜皱缩,整个晶体囊膜出现纺锤形细胞。术后7d时后囊膜明显混浊,见较多纺锤形细胞分布。所有动物于术后14d出现明显后囊膜皱缩,可见新生晶体纤维。术后28d见明显后囊膜增厚,新生晶体纤维填充囊袋,后囊膜未见细胞。LEC形态及分布恢复到术后0h状态。免疫组化检测见术后3d时α-SMA阳性表达。结论:改良法成功建立大鼠PCO模型,LEC在PCO形成中出现形态和分布上的动态变化。其将为在分子水平上探索PCO的发病机制及防治方法提供合适研究载体。     

Effect of Liposome—Encapsulated Total Alkaloid of Harmaline on Rabbit Lens Epithelial Cells：Experimental Study on the Prevention of Posterior Capsule Opacification

Purpose: To investigate whether liposome encapsulated total alkaloid of Harmaline (TAH) as a therapeutic agent is beneficial to prevention of posterior capsular opacifi-cation (PCO).Methods: Liposome-encapsulated TAH was prepared by modified freeze-thawing method. 0. 1ml of liposome-encapsulated TAH (0. 2mg/ml) was injected into the capsular bag during extracapsular lens extraction (ECLE) of each eye in total 10 rabbit eyes. Blank liposome or balance salt solution (BSS) was used as control. Slit-lamp examination and histopathological examination was used to evaluated capsule opacifica-tion. Intraocular pressure (IOP) , density and morphology of corneal endothelia cells, the amplitude and latency of b wave of ERG were measured.Results: The inflammatory response was mild both in TAH treated and the control group. PCO formation occurred in the control group 2 weeks postoperatively, but the posterior capsule was clear in TAH treated eyes. 4 weeks and 8 weeks after operation, PCO occurred both in TAH treated     

超声乳化术中前囊膜抛光预防后囊膜混浊的临床研究

目的探讨在白内障超声乳化术中行前囊膜抛光处理减少后发障发生的有效性和安全性.方法178例(235只眼)白内障患者在施行白内障超声乳化吸除及人工晶状体植入术中进行前囊膜抛光,术后对其视力、眼前节反应及后囊膜情况进行临床观察,随访1个月～1年,选择同期未行前囊膜抛光者220例(230只眼),作为对照组进行比较.结果(1)术中无并发症发生;(2)术后视力恢复快而良好;(3)术后后囊膜混浊发生8只眼(3.5%),均为轻度纤维型混浊,对视力无显著影响,而对照组术后后囊膜混浊发生23只眼(10.2%).对照组显著高于抛光组(P＜0.05).结论白内障超声乳化术中行前囊膜抛光处理可以减少术后后囊膜混浊的发生.作用机制可能是前囊膜抛光可大幅度地减少残留于前囊下的晶状体上皮细胞数量,阻止了上皮细胞的增殖及化生的来源,从而起到防止后囊膜混浊发生的作用.     

The Protective Effect of Metformin Use on Early Nd:YAG Laser Capsulotomy

PurposeTo determine the effect of metformin on early Nd:YAG laser treatment for posterior capsule opacification (PCO) and to explore a molecular mechanism to explain a possible protective effect of metformin against PCO.MethodsWe conducted: 1) a retrospective cohort study of patient eyes undergoing phacoemulsification at our institution; and 2) laboratory investigation of the effect of metformin on the behavior of lens epithelial cells in the context of an animal model for PCO. Population-averaged Cox proportional hazards modeling was used to estimate risk for time to Nd:YAG. For laboratory studies, expression of markers for epithelial-to-mesenchymal transition (EMT) implicated in PCO pathogenesis was measured in tissue culture and following extracapsular lens extraction in a mouse model.ResultsThe rate of Nd:YAG laser capsulotomy was 13.1% among the 9798 eyes. Both metformin use and diabetes were protective factors for Nd:YAG laser capsulotomy in univariate analysis. However, in multivariable analysis with nondiabetics as the reference group, only metformin use among diabetics was significantly protective of Nd:YAG (hazard ratio: 0.68, 95% CI: 0.54–0.85, P = 0.0008), while eyes of patients with diabetes without metformin use did not significantly differ (P = 0.5026). Treatment of lens epithelial cells with metformin reduced the level of the EMT markers ⍺-SMA and pERK induced by TGF-β2. Similarly, metformin treatment reduced ⍺-SMA expression in lens epithelial cells following extracapsular lens extraction in a mouse model.ConclusionsThe protective effect of metformin against early Nd:YAG may relate to its ability to downregulate EMT in residual lens epithelial cells that otherwise trend toward myofibroblast development and PCO.