Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Inhibitory effect on subretinal fibrosis by anti-placental growth factor treatment in a laser-induced choroidal neovascularization model in mice

AIM:To investigate whether anti-placental growth factor(PGF) can inhibit subretinal fibrosis and whether this effect is mediated by the inhibitory effect of PGF on epithelial-mesenchymal transition(EMT) of retinal pigment epithelial(RPE) cells.METHODS:Subretinal fibrosis model was established in laser induced choroidal neovascularization(CNV) mice on day 21 after laser photocoagulation.Immunofluorescence staining(IFS) of cryosections and enzyme-linked immunosorbent assay(ELISA) were used to detect the expression of PGF.IFS of whole choroidal flat-mounts was used to detect the degree of subretinal fibrosis.IFS of cryosections and ELISA were used to detect the expression of EMT related indicators in subretinal fibrosis lesions.RESULTS:The expression of PGF protein in subretinal fibrosis lesions was significantly up-regulated(P<0.05),and mainly co-stained with pan-cytokeratin labeled RPE cells.Intravitreal injection of anti-PGF neutralizing antibody reduced the area of subretinal fibrosis and the ratio of fibrotic/angiogenic area significantly at the concentrations of 0.25,0.5,1.0,and 2.0 μg/μL(all P<0.05).The expression of E-cadherin in the local RPE cells decreased,while α-SMA increased significantly in subretinal fibrosis lesions,and the application of anti-PGF neutralizing antibody could reverse these changes(P<0.05).CONCLUSION:The expression of PGF is up-regulated in the lesion site of subretinal fibrosis and mainly expressed in RPE cells.Intravitreal injection of anti-PGF neutralizing antibody can significantly inhibit the degree of subretinal fibrosis in CNV mice,and this effect may be mediated by the inhibition of PGF on EMT of RPE cells.

Modified Vitreous Surgery for Subretinal Neovascularization and Hemorrhage

Purpose:To modify vitreous surgery for subretinal neovascularization(SRNV)and to detrmine the effects of this operation.Methods:Six patients with SRNV were performed with this operation,The meth-ods of examination before and after operation included;testing the best-corrected visual acuity before operation and 1,3or6months after operation;30degrees and visual acuity before operation and 1,3or6months after operation;30degrees and macular 10degrees Humphrey visual field examination:FFA examination preop-eratively and 1,3or6months postoperatiely.Modified surgery procedureis;a preventive buckling;pars plana vitrectomy;peeling the vitreous cortical;no in-traocular diathermy;small retinotomy;subretinal surgery;air-fluid exchang.Results:SRNV was taken off in4cases.Subretinal hemorrhage was washed in2cases.After4to7months follow-up,the visual acuity was improved in 4cases,unchanged in 2cases.The visual field was improved in 4cases.unchanged in 1case,decraesed in 1case,The complications included macular hole due to surgery in lcase and subretinal hemorrage in 1case.Conclusion;The surgery criteria were:1)massive subretinal hemorrhage;2)some patients of SRN V included;FFA evidence they showed the membrane is beneath fovea,the bestV.Ais20/100orlower.and can't be treated by laser and the pa-tient consent.This modified subretinal operation is safe,and effective for massive hemorrhage and some SRNVS.

黄斑、视盘旁与周边脉络膜新生血管

本文结合文献与个人经验总结了黄斑、视盘旁与周边脉络膜新生血管(CNV)的临床表现与治疗。黄斑CNV:本文重点讨论了那些对抗血管内皮生长因子(VEGF)治疗无反应患者的原因及对策;并介绍了息肉样脉络膜血管病变(PCV)的光学相干层析成像(OCT)的特征及目前的最佳治疗方案。视盘旁CNV:介绍了本病眼底表现,荧光素眼底血管造影(FFA)及OCT所见,常见病因及治疗。周边CNV:则介绍了临床表现、疾病转归,治疗及预后特别是与脉络膜黑色素瘤的鉴别诊断做了较详尽的讨论。并简短提到,近期研究认为周边渗出性出血性脉络膜视网膜病变(PEHCR)可能属于厚脉络膜频谱病群中的一员。

Volumetric fluid analysis of fixed monthly anti-VEGF treatment in patients with neovascular age-related macular degeneration

·AIM:To evaluate visual outcomes and changes in fluid after administering monthly anti-vascular endothelial growth factor(VEGF)injections to treat neovascular agerelated macular degeneration(n AMD)with subretinal fluid(SRF)and pigment epithelial detachment(PED).·METHODS:This prospective study included eyes with n AMD previously treated with as-needed anti-VEGF injections.The patients were treated with six monthly intravitreal injections of ranibizumab.Quantitative volumetric segmentation analyses of the SRF and PED were performed.The main outcome measures included best-corrected visual acuity(BCVA),and SRF and PED volumes.·RESULTS:Twenty eyes of 20 patients were included in this study.At the 6-month follow-up,BCVA and PED volume did not change significantly(P=0.110 and 0.999,respectively)but the mean SRF volume decreased from 0.53±0.82 mm3 at baseline to 0.08±0.23 mm3(P=0.002).The absorption rate of the SRF volume was negatively correlated with the duration of previous antiVEGF treatment(P=0.029).Seven of the 20 eyes(35%)showed a fluid-free macula and significant improvement in BCVA(P=0.036)by month 6.·CONCLUSION:Quantifying the SRF can precisely determine the patient’s responsiveness to anti-VEGF treatment of n AMD.

上皮-间质转化在视网膜下纤维化发病机制中的研究进展

视网膜下纤维化(SRFi)被定义为视网膜内或视网膜下混合的纤维血管结构,本质是新生血管性年龄相关性黄斑变性(nAMD)中脉络膜新生血管形成后伤口过度愈合的结果,这是导致nAMD患者终末期视力丧失的主要原因。nAMD患者终末期视网膜色素上皮细胞向上皮-间质细胞转化的过程被认为是影响SRFi形成的主要细胞基础。针对SRFi中上皮-间质转化的相关细胞及分子机制研究可能是未来终末期nAMD疾病防治的重要发展方向。

湿性年龄相关性黄斑变性视网膜下纤维化的研究进展

年龄相关性黄斑变性(age-related macular degeneration,AMD)是一种发生在黄斑区的退行性变,其中湿性年龄相关性黄斑变性(wet age-related macular degeneration,w AMD)以黄斑区新生血管为主要病理特征,是导致老年人视力受损甚至失明的重要原因,视网膜下纤维化是w AMD最常见的自然后遗症,可导致光感受器、视网膜色素上皮(retinal pigment epithelial,RPE)和脉络膜毛细血管受损,导致不可逆转的中心视力丧失。多种基线特征被发现是视网膜下纤维化的危险因素,可用于预测早期视网膜下纤维化的发生。迄今为止,还没有有效的抗纤维化治疗方法,抗血管内皮生长因子(anti-vascular endothelia growth factor,anti-VEGF)治疗是w AMD的一线治疗方案,该治疗方法不能改善视网膜下纤维化,但及时启动治疗可能有助于预防或延缓纤维化的进展,目前多种靶向分子药物正被研发用于抗纤维化的治疗。该文综述了w AMD视网膜下纤维化的临床表现及意义、预测纤维化形成的基线特征、基本发病机制及潜在的抗纤维化治疗方法,旨在为临床诊治工作提供参考。

氩激光诱发兔视网膜下新生血管的眼底荧光血管造影

目的：探讨视网膜下新生血管（ＳＲＮＶ）的发病机理及发生、发展特点．方法：用高强度氩激光光凝兔视网膜，经眼底镜及眼底荧光血管造影（ＦＦＡ）观察．结果：光斑出血发生率为２７％．光凝后１周，ＦＦＡ脉络膜期及动脉早期８％的光斑有点状荧光素渗漏．光凝后３周，６３％的光斑出现脉络膜新生血管（ＣＮＶ）形态．直至２个月，渗漏区逐渐扩大．光凝后３～４个月时，渗漏范围渐缩小．结论：ＣＮＶ的发生时间为１周．兔眼的ＳＲＮＶ发生率较高（６３％），是研究ＳＲＮＶ的理想模型．其发展过程可分为活动期及退化期，时间各为８～１０周左右．

bFGF诱导兔眼视网膜下新生血管形成的实验研究

目的探讨碱性成纤维细胞生长因子（bFGF）诱导青紫兰兔视网膜下新生血管动物模型的方法及可行性。方法健康成年青紫兰兔40只，随机分为2组。第1组实验组兔眼视网膜下注入0．005％（wt／vol）bFGF50μl，第2组对照组兔眼视网膜下注入0．9％生理盐水50μl，对侧眼均作为空白对照，不行视网膜下注射。术后3d，1、2、3、4、6、8、12周分别行眼底检查、摄片、眼底荧光血管造影（FFA）和吲哚青绿血管造影（ICGA），并行眼球组织病理学检查。结果视网膜下注射后所有眼即见视网膜直径4～5PD的青灰色半球形隆起，实验组与对照组分别于注射后2周和1周后平伏。术后2～12周FFA造影可见实验眼于视网膜隆起处下方早期斑点状高荧光，后期荧光增强并融合扩大。ICGA显示FFA高荧光相应部位荧光染料积存。对照组眼FFA、ICGA造影检查均未见类似表现。病理检查结果显示：视网膜下注射bFGF后2～12周，实验眼视网膜感光细胞层下有新生血管形成。结论视网膜下注入bFGF能成功诱导青紫兰兔视网膜下新生血管形成。

病理性近视的黄斑部视网膜下新生血管

目的 研究病理性近视黄斑区脉络膜新生血管的临床特点及发病机制。方法 对1 2 1只眼的高度近视患者作视力、眼底检查及荧光素眼底血管造影检查 ,并分析其临床特点。结果 观察病例中病理性近视黄斑区视网膜下新生血管发生的构成比为 3 0 6%。病理性近视黄斑区视网膜下新生血管与近视度数、漆样裂纹形成、黄斑区缺血等因素有关。结论 发生于中心凹的新生血管出血是严重影响视力的主要原因。

高度近视黄斑出血相关因素分析

目的对高度近视黄斑出血的相关因素进行分析。方法对55例(69眼)高度近视黄斑出血的患者进行视力、屈光度、A/B超、眼底彩色照相及荧光素眼底血管造影(fundusfluoresceinangiography,FFA)检查。结果43例(78.2%)近视病程超过20年,54眼(78.3%)眼轴超过29mm,44眼(63.8%)出现后巩膜葡萄肿,所有患者屈光度均超过-10D,黄斑出血时8眼(11.6%)可见漆样裂纹,6眼(8.7%)显示视网膜下新生血管(subretinalneovaseularization,SRNV)。出血吸收后19眼(27.5%)可见漆样裂纹,9眼(13.0%)出现SRNV。结论近视病程超过20年、眼轴超过29mm、屈光度超过-10D、有后巩膜葡萄肿的患者容易发生黄斑出血,漆样裂纹与高度近视黄斑出血有密切的关系。高度近视黄斑出血分为两种类型:一种是不伴SRNV的单纯型出血,另一种是伴有SRNV的出血。单纯型黄斑出血预后较好,伴有SRNV的黄斑出血预后差,定期检查眼底及FFA,有助于早期发现SRNV。

视网膜血管瘤增殖—年龄相关性黄斑变性的特殊类型

本文总结了年龄相关性黄斑变性的特殊类型—视网膜血管瘤增殖(RAP)的临床和造影表现及分期。RAP是起源于黄斑旁视网膜深层毛细血管的、以伴发多灶小片视网膜内出血及盘变前期即有视网膜-脉络膜血管吻合(RCA)形成为特征的新生血管性AMD。

实验性视网膜下新生血管的组织病理学观察

目的探讨视网膜下新生血管（SRNV）的发病机理。方法用高强度氩激光光凝兔视网膜，经眼底镜，光、电镜观察眼底变化及视网膜、脉络膜超微结构改变。结果光斑出血发生率为27％。光凝后1～3天，光镜下光班区Bruch膜及视网膜色素上皮（RPE）层断裂，视网膜、脉络膜组织严重破损，水肿、出血、毛细血管闭塞。电镜下光感受器细胞内、外节溶解，白细胞浸润、巨噬细胞聚集。光斑边缘RPE细胞线粒体空泡变性。光凝后1周，新生血管长入光斑边缘。结论高强度激光所造成的视网膜外层破坏、局部缺血、炎性反应、出血等，在SRNV的发病机理中具有重要作用。

视网膜血管瘤增殖的研究进展

视网膜血管瘤增殖是近年来开始为人们所认识的一类新型新生血管性年龄相关性黄斑变性,它起源于黄斑旁视网膜深层毛细血管网并能不断增殖,向后突破入视网膜下间隙,最终与脉络膜新生血管形成吻合。本文对视网膜血管瘤增殖的分期、临床表现以及治疗方法作一综述。

新生血管性年龄相关性黄斑变性相关的视网膜下纤维化的研究进展

新生血管性老年性黄斑变性(nAMD)导致的严重视力损害与黄斑新生血管(MNV)的侵袭及视网膜下纤维化(SF)有关。过度的SF可导致视网膜下瘢痕形成,使光感受器、视网膜色素上皮和脉络膜组织发生不可逆性损害,使得nAMD患者出现永久视力障碍。SF发生机制复杂,涉及组织损伤后修复、炎症等诸多病理学过程,与之相关的信号通路及细胞因子。目前对于SF的实验性治疗仅针对单个细胞因子的抑制。及时有效抑制MNV的生成及进展,早期识别SF发生的危险因素,对改善nAMD患者的预后至关重要。

细胞外基质在年龄相关性黄斑变性中的研究进展

年龄相关性黄斑变性(ARMD)是老年人失明的主要原因。研究表明,细胞外基质(ECM)调节障碍作为ARMD疾病的重要特征之一,它的损伤可贯穿于ARMD病程。此外,参与ARMD发生发展过程的各类型细胞可以在多种信号的控制下参与ECM的形成与异常沉积,通过传递调节黏附、迁移、增殖、凋亡、存活或分化的信号,从而导致视网膜、脉络膜微环境的破坏,免疫功能障碍,浸润性炎症细胞分化,新生血管生成,上皮-间充质转化,最终导致晚期ARMD视网膜下纤维化和瘢痕形成及视力严重受损。因此,ECM在ARMD中的作用逐渐引起重视。文章针对视网膜中ECM与ARMD的联系及ARMD中各类型细胞与ECM之间的作用做一综述,以期为治疗ARMD的研究方向提供指导意义。

新生血管性年龄相关性黄斑变性中视网膜下高反射物质的研究进展

视网膜下高反射物质(SHRM)是光学相干断层扫描中显示的一种高反射性形态学特征,位于神经上皮外层、色素上皮内层。其常见于未经治疗或经抗血管内皮生长因子治疗后的新生血管性年龄相关性黄斑变性(nAMD),也可见于中心性浆液性脉络膜视网膜病变、葡萄膜炎、近视性脉络膜新生血管、近视性黄斑变性、Best病、视网膜营养不良和脂质肉芽肿病等。SHRM与患者眼部椭圆体带缺失、瘢痕形成、外界膜损伤、黄斑萎缩及外层视网膜管型结构等关系密切,并与视力损害显著相关。抗血管内皮生长因子治疗可显著消退部分SHRM,不同成分及特征的SHRM对治疗有不同的预后反应。明确nAMD中SHRM的形态特征及其功能后果,进一步加深临床对SHRM的认识。

光学相干断层扫描血管成像在2型黄斑毛细血管扩张症中的应用进展

2型黄斑毛细血管扩张症(MacTel 2)是一种双侧、进展缓慢的视网膜神经退行性疾病,血管病变是其主要特征。光学相干断层扫描血管成像(OCTA)是检测MacTel 2的理想工具。OCTA显示,MacTel 2的毛细血管扩张最早出现在旁中心凹颞侧的深层毛细血管丛,与椭圆体带丢失密切相关。随后出现的旁中心凹血管密度降低最先累及小静脉相邻的毛细血管。而直角小静脉的发展可促进视网膜-脉络膜吻合形成。一部分晚期MacTel 2患者可进展为新生血管,而使用血管内皮生长因子(VEGF)抑制剂对未经治疗的新生血管效果显著。现就OCTA近期在MacTel 2中的应用进行综述。

氪红激光透热治疗视网膜下新生血管及脉络膜血管瘤的疗效分析

目的 :观察用氪红激光大光斑、低能量、长时间照射眼底视网膜下新生血管 (SRNV )及脉络膜血管瘤的治疗效果。方法 :选用经临床眼底检查、FFA检查 (部分作ICG检查 )证实的视网膜下新生血管病例 2 0例 ,其中渗出型增龄性黄斑变性(AMD) 14例 ,高度近视黄斑出血 4例 ,中心性渗出性视网膜脉络膜病变 (中渗 ) 2例 ;另有 2例孤立性脉络膜血管瘤。使用氪红激光经瞳孔照射病灶部位。所用激光参数为 ,光斑直径 75 0～ 10 0 0 μm、功率 75～ 10 0mW、照射时间 2 0～ 3 0S ,根据病灶范围大小确定激光点数 ,RNV激射 1～ 6点 ,平均 3点 ,脉络膜血管瘤激射 2 0～ 46点不等。术后复查视力、眼底检查、FFA (及ICG)检查 ,评价治疗效果。结果 :2 2例中有随访记录的 18例 ,随访 12例AMD中治愈 7例 ,好转 4例 ,视力下降 1例 ;中渗 2例中治愈 1例 ,好转 1例 ;高度近视 2例中治愈 1例 ,好转 1例 ;2例脉络膜血管瘤均获治愈。结论 :使用大光斑、低能量、长时间氪红激光治疗视网膜下新生血管病变及脉络膜血管瘤 ,对新生血管的萎缩、保存和恢复视力疗效可靠 ,副作用小。

玻璃体切割手术后视野缺损

目的：报告扁平部玻璃体切割手术治疗黄斑裂孔、视网膜下新生血管膜及视网膜前膜，术后发生视野缺损的发生率，并探讨其发病机理。方法：所有病人于术后２个月后接受Ｇｏｌｄｍａｎｎ视野检查，术前影响视野的疾病如青光眼不包括在本研究中。临床资料包括诊断、术前术后视力、手术过程，以及术前术后眼压。结果：在４８例病人５０只眼中，共９只眼（１８％）术后发生视野缺损，其中黄斑裂孔组２１只眼中有４只眼（１９％），视网膜下新生血管膜组１３只眼中有５只眼（３８％），视网膜前膜组１６只眼术后均无视野缺损（ｐ＜０．０５）；视野损害与年龄及术前术后眼压无关。结论：玻璃体切割手术后视野缺损多发生在术中有气液交换的病例，气液交换过程中，在吸除视神经表面液体时。