角膜淋巴管新生在眼部疾病中的研究进展

角膜淋巴管新生在眼部疾病中发挥重要作用。通常情况下,角膜是一种无血管、无淋巴管的组织,这种无血管、无淋巴管的状态对角膜的透明性和功能性至关重要。然而,一些疾病或创伤可能引起角膜血管和淋巴管的新生,从而破坏角膜的结构和功能。尽管已有多种针对角膜血管新生的药物在临床应用,但尚无特异性针对角膜淋巴管新生的药物。因此,本综述将介绍与角膜淋巴管新生相关的因素,探讨与之相关的眼部疾病,同时对目前的治疗现状进行分析,旨在为淋巴管新生相关的眼部疾病治疗提供更多的选择和可能性,为基于角膜淋巴管新生的研究和药物开发提供参考。     

角膜新生淋巴管的研究进展

近年来随着淋巴管内皮细胞特异性标记物VEGFR-3、LYVE-1、Podoplanin和Prox 1等的发现，对于角膜新生淋巴管的研究有了较大进展，成为近几年的研究热点。本文就角膜新生淋巴管是如何生成，其与新生血管之间的关系，新生淋巴管在角膜移植免疫排斥反应发生过程中的作用作一综述。     

角膜新生淋巴管的分子免疫学研究进展

角膜新生淋巴管构成了角膜免疫反应的传入弧,它与角膜新生血管的协同作用是破坏角膜免疫赦免机制的关键因素.近年来,随着淋巴内皮细胞特异性标志物的相继发现,有关角膜淋巴管生成因子的生物学特性、调节机制及临床意义等方面的研究有很大进展.角膜新生淋巴管的免疫调节作用及与移植排斥反应的关系成为研究热点.为此,本文结合角膜免疫赦免特点对角膜新生淋巴管生成的调控机制及其与角膜移植排斥反应之间的关系作一综述.     

角膜新生淋巴管的研究进展

角膜新生淋巴管多见于感染、炎症、外伤或角膜移植术后.临床上,如何有效的防治角膜移植术后排斥反应是角膜移植手术成功的关键.随着近年来角膜新生淋巴管内皮特异性标记物及重要淋巴管生长因子的相继发现,人们对角膜新生淋巴管的生成机制及与角膜移植排斥反应的关系有了深入的研究,此文就新生淋巴管的生成及其在角膜移植排斥中的作用作一综述.     

角膜新生淋巴管的研究进展

近年来随着淋巴管内皮细胞特异性标记物VEGFR-3、LYVE-1、Podoplanin和Prox 1等的发现,对于角膜新生淋巴管的研究有了较大进展,成为近几年的研究热点。本文就角膜新生淋巴管是如何生成,其与新生血管之间的关系,新生淋巴管在角膜移植免疫排斥反应发生过程中的作用作一综述。     

同种异体角膜移植术后角膜新生淋巴管的实验研究

目的 探讨新西兰大白兔角膜碱烧伤后及同种异体角膜移植术后角膜新生淋巴管(CL)上VEGFR3、LYVE-1及CD4的表达及意义,从而进一步证实角膜碱烧伤和高危角膜移植后角膜新生淋巴管的存在及与排斥反应的关系.方法 饲养96只健康新西兰大白兔,将其随机分为5组.空白对照组24只,选取实验1组24只右眼,不做手术;实验1组24只,左眼制作角膜碱烧伤模型;实验2组24只,左眼进行钻取自体角膜后再缝合;实验3组24只,左眼进行同种异体角膜移植;实验4组24只,左眼进行高危(角膜碱烧伤后)同种异体角膜移植.术后第1、3、7、14天各组分别处死6只兔,进行大体观察、裂隙灯、组织学、电镜检查及免疫组化测定LYVE-1、VEGFR3及CD4的表达情况.结果 (1)空白对照组在术后不同时间LYVE-1、VEGFR3和CD4均无表达.(2)实验1、2、3组:LY-VE-1、VEGFR3和CD4分别于术后第1天未出现表达,第3天出现表达,第7、14天表达增高;(3)实验4组:LYVE-1、VEGFR3和CD4分别于术后第1天开始出现表达,第3、7、14天表达逐渐增高.(4)实验1、2、3组术后第3、7、14天LYVE-1、VEGFR3和CD4表达均高于空白对照组.(5)实验4组术后第1、3、7、14天LYVE-1、VEGFR3和CD4表达均高于空白对照组.(6)实验3组较实验1、2组术后14天LYVE-1、VEGFR3和CD4表达增高.(7)实验4组较实验1、2、3组术后同时期LYVE-1、VEGFR3和CD4表达均增高.结论 角膜移植术后存在CL,且在术后2周内随时间延长逐渐增多,CL可能直接参与角膜移植术后排斥反应.     

新生淋巴管与角膜移植排斥的研究进展

角膜新生淋巴管构成了角膜免疫反应的传入弧,在免疫反应中发挥了重要作用。由于新生淋巴管的出现破坏了免疫机制使角膜移植术后排斥反应发生率升高。随着淋巴管内皮标记物的相继出现和对淋巴管生成因子的研究深入,众多学者对角膜淋巴管在角膜免疫排斥反应机制、治疗和预防等方面进行了大量研究,通过抑制新生淋巴管提高植片存活率。     

角膜移植后患者角膜新生淋巴管与新生血管和炎症的关联

目的:研究角膜移植后角膜新生淋巴管与新生血管和炎症的关联。方法:人角膜取自行二次角膜移植的患者19例。淋巴内皮细胞受体(lymphatic vessel endothelial hyaluronan receptor,LYVE-1)和内皮细胞黏附因子-1(platelet endothelial celladhesion modecule-1,PECAM-1)双重免疫组化法标记角膜中的新生血管和淋巴管,进行淋巴管计数(lymphatic ves-sels counting,LVC)和血管计数(blood vessels counting,BVC),比较BVC、炎症指数(inflammation index,IF)、移植历史(transplantation history,TH)与LVC之间的关联。结果:角膜移植后BVC,IF与LVC间均呈显著性正相关,而TH与LVC间呈显著性负相关。角膜移植后新生淋巴管、血管、眼表炎症间大致成平行发展,新生淋巴管最先退化,其次是眼表炎症,新生血管最后消退。结论:人角膜移植后角膜新生淋巴管与新生血管、眼表炎症之间存在着极为密切的关联。     

碱烧伤后角膜新生淋巴管的实验研究

目的动态检测大鼠角膜碱烧伤后的角膜新生淋巴管和血管的变化,并阐明二者之间的关联。方法制备大鼠角膜碱烧伤模型,于碱烧伤后1周、2周行角膜组织电镜检查,检测角膜新生淋巴管与新生血管。5’核苷酸酶-碱性磷酸酶(5’-nase-alkaline phos-phatase,5’-NA-ALP)双重酶组织化学染色及全角膜免疫荧光染色分别检测碱烧伤后6h、1d、3d、1周、2周、3周、4周、5周、6周、7周、8周的角膜新生淋巴管和新生血管的动态变化,并进行淋巴管计数(lymphatic vessels counting,LVC)和血管计数(blood vessels counting,BVC)比较。结果电镜观察结果:角膜碱烧伤后1周,角膜基质层出现新生血管,未见淋巴管;碱烧伤后2周,新生血管和新生淋巴管均出现。酶组织化学染色结果显示:碱烧伤后6h有新生血管,1周时角膜基质层存在新生淋巴管,2周时LVC和BVC均达到高峰,分别为(16.41±1.00)个和(50.40±1.56)个;以后逐渐下降,5周时LVC为(0.33±0.50)个,BVC为(12.52±2.51)个;8周时均为0。碱烧伤后,新生淋巴管和新生血管呈显著性正...     

角膜移植后角膜新生淋巴管与新生血管间的关联

目的:研究角膜移植后角膜新生淋巴管与新生血管间关联。方法:人角膜取自行二次角膜移植的19名患者。5核苷酸酶-碱性磷酸酶(5-nase-Alkaline phosphatase,5-NA-ALP)双重酶组织化学染色及淋巴内皮细胞受体(lymphatic vessel endothelial receptor,LYVE-1)、内皮细胞黏附因子-1(platelet endothelial cell adhesion modecule-1,PECAM-1)双重免疫组化法标记角膜中的新生血管和淋巴管,并进行淋巴管计数(lymphatic vessels counting,LVC)和血管计数(blood vessels counting,BVC),比较BVC与LVC之间的关联。结果:角膜中存在角膜新生血管12例(63%),存在角膜新生淋巴管5例(26%)。角膜新生淋巴管仅出现在血管化角膜中。角膜移植后BVC与LVC间呈显著性正相关(r=0.725;P<0.01)。结论:人角膜移植后角膜新生淋巴管与新生血管之间存在密切关联。     

Corneal lymphangiogenesis in dry eye disease is regulated by substance P/neurokinin-1 receptor system through controlling expression of vascular endothelial growth factor receptor 3

PurposeTo evaluate the role of substance P (SP)/neurokinin-1 receptor (NK1R) system in the regulation of pathologic corneal lymphangiogenesis in dry eye disease (DED).MethodsImmunocytochemistry, angiogenesis assay, and Western blot analysis of human dermal lymphatic endothelial cells (HDLECs) were conducted to assess the involvement of SP/NK1R system in lymphangiogenesis. DED was induced in wild-type C57BL/6 J mice using controlled-environment chamber without scopolamine. Immunohistochemistry, corneal fluorescein staining, and phenol red thread test were used to evaluate the effect of SP signaling blockade in the corneal lymphangiogenesis. The expression of lymphangiogenic factors in the corneal and conjunctival tissues of DED mouse model was quantified by real-time polymerase chain reaction.ResultsNK1R expression and pro-lymphangiogenic property of SP/NK1R system in HDLECs were confirmed by Western blot analysis and angiogenesis assay. Blockade of SP signaling with L733,060, an antagonist of NK1R, or NK1R-targeted siRNA significantly inhibited lymphangiogenesis and expression of vascular endothelial growth factor (VEGF) receptor 3 stimulated by SP in HDLECs. NK1R antagonist also suppressed pathological corneal lymphangiogenesis and ameliorated the clinical signs of dry eye in vivo. Furthermore, NK1R antagonist effectively suppressed the lymphangiogenic factors, including VEGF-C, VEGF-D, and VEGF receptor 3 in the corneal and conjunctival tissues of DED.ConclusionsSP/NK1R system promotes lymphangiogenesis in vitro and NK1R antagonism suppresses pathologic corneal lymphangiogenesis in DED in vivo.     

联合自—异体板层角膜移植减少排斥反应研究

目的观察联合自异体板层角膜移植术对植片免疫排斥反应的发生率及疗效。方法对２３例（２４只眼）已切除侵犯瞳孔区的翼状胬肉及中央板层角膜患者,分别在周边和中央行自异体植片移植术。另与单纯行胬肉或角膜皮样瘤切除、原位异体板层角膜移植术的１３例（１３只眼）患者进行对照,比较其排斥反应的发生率和疗效。结果自异体移植组的植片全部透明,无一例发生排斥反应和翼状胬肉复发。对照组则有３０．８％发生排斥反应,２０．０％翼状胬肉复发。结论联合自异体板层角膜移植术可减少排斥反应及翼状胬肉的复发     

角膜磨削联合角膜缘干细胞移植术治疗翼状胬肉疗效观察

目的评价角膜磨削联合角膜缘干细胞移植术治疗翼状胬肉的临床疗效,寻找低复发率的治疗方法。方法对接受翼状胬肉手术治疗的124例（195只眼）分别进行手术前后视力、泪液分泌（SchirmerⅠ）试验、泪膜破裂时间（BUT）及角膜地形图变化的比较;并对其中的30例（49只眼）专项进行了手术前后视力和角膜平均散光的观察。结果术后4只眼复发,占2.1%;做专项光学比较的49只眼中除5只眼因翼状胬肉太大测不出之外,其余44只眼均有不同程度的散光,以顺规性散光为主。角膜地形图检查平均散光：术前为（3.40±2.76）D,术后1周为（1.41±1.27）D,术后1个月为（1.05±1.04）D,术后3个月为（1.02±0.98）D;术后1周、1个月与术前的差异均具有统计学意义（P（0.05）;术后1周、1个月之间的差异有统计学意义（P（0.05）;1个月与3个月之间的差异无统计学意义（P=0.062（0.05）。平均最佳矫正远视力：术前为（0.55±0.25）,术后1周为（0.67±0.21）,术后1个月为（0.80±0.23）,术后3个月为（0.81±0.21）;术后1周、1个月与术前的差异均具有统计学意义（P（0.05）;术后1周、1个月之间的差异有统计学意义（P（0.05）;1个月与3个月之间的差异无统计学意义（P=0.090（0.05）。角膜上皮愈合时间平均为3.78d;BUT恢复时间为（4.6±0.8）d。结论角膜磨削联合角膜缘干细胞移植术治疗翼状胬肉术后复发率低,角膜上皮修复快,散光得以改善,视力提高,是一种值得推广的安全有效的手术方法。     

Age-related changes in murine limbal lymphatic vessels and corneal lymphangiogenesis

Important risk factors for graft rejection after corneal transplantation are pathologic corneal lymphangiogenesis and young recipient age. Purpose of this study was to investigate whether there are age-related differences in normal murine limbal and pathologic corneal lymphatic vessels, which could partly explain the unequal outcome of corneal transplantation in young versus old recipients. Furthermore, we investigated whether these observed differences correlate with changes in allograft survival in the murine model of corneal transplantation. Corneal whole mounts from untreated young (aged 6-8 weeks), untreated old (aged 9-15 months) and young and old mice after suture-induced, inflammatory corneal neovascularization were prepared and stained with LYVE-1 as a lymphendothelial marker. Angles of corneal parts with and without a main circumferential limbal lymphatic vessel were measured and then related to the total 360° of corneal circumference. Centrally directed vascular extensions from the main limbal lymphatic vessel (“sprouts”) of previously untreated old mice were counted. Concerning the outgrowth of pathologic lymphatic vessels after inflammatory corneal neovascularization, the area covered with pathologic lymphatic vessels was detected by an algorithm on digitized whole mounts using cell^F^® software. Low-risk allogeneic (C57Bl/6 to BALB/c) corneal transplantations were performed with one recipient group being young, the other group being old mice. In young, untreated mice, 70.5% of the total corneal circumference was covered by a main circumferential limbal lymphatic vessel versus 60.8% in old, untreated mice. Comparing the number of centripedal vascular extensions from the main limbal lymphatic vessel (“sprouts”), untreated old mice had significantly less extensions than young, untreated mice (p < 0.001). After an inflammatory stimulus, old mice had significantly less pathologic corneal lymphatic vessels than young mice (42% less, p < 0.001). Comparing the survival proportions after corneal transplantation, old recipient mice showed a significantly better graft survival 6 weeks after transplantation (65% versus 33%, p < 0.05). Thus, limbal lymphatic vascular sprouts and inflammation-induced pathologic corneal lymphangiogenesis decrease with age. The lower lymphangiogenic potency of older mice may explain the better outcome of corneal transplantations in old recipients, supporting the concept that lymphangiogenesis is an important risk-factor for corneal transplant rejection.     

角膜神经改变与干眼的研究进展

角膜表面具有丰富的神经末梢,是人体全身中最敏感的部位之一,对外界刺激反应迅速且强烈。干眼是一种复杂的多因素疾病,其症状与体征的变化及其严重程度不相符,诊断和治疗难度极大。近年来,有关干眼与角膜神经关系的研究备受关注;同时患有其他系统疾病者亦有眼干症状,表现为角膜神经改变。这对全身疾病的诊断和治疗有重要意义。因此,本文中笔者从角膜神经改变角度阐述开发干眼治疗和全身疾病进展监测方法的可行性。     

自体角膜缘干细胞滑行移植治疗翼状胬肉临床观察

目的比较自体角膜缘干细胞滑行移植术和传统角膜干细胞移植术治疗翼状胬肉的疗效。方法将166例218眼翼状胬肉患者随机分成A、B组：A组58例78眼行自体角膜缘干细胞滑行移植术切除,B组108例140眼行传统角膜干细胞移植术切除。观察伤口愈合情况及复发率。结果术后观察6月-12月,A组78眼中复发1眼,B组140眼中复发6眼,两组复发率比较,差异无统计学意义（χ^2=1.454,P〉0.05）。结论自体角膜缘干细胞滑行移植术具有简便快捷,创伤小,恢复快,术后刺激症状轻,愈合后无明显疤痕,复发率低等优点,值得在临床上推广。     

Geographic distribution of corneal staining in symptomatic dry eye

PurposeTo describe the geographic distribution of corneal fluorescein staining across the five corneal zones, among non contact lens wearers who report symptoms of dry eye and determine which corneal zone most frequently exhibited the worst staining.MethodsPrior studies conducted at the Centre for Ocular Research & Education, Canada, were reviewed for inclusion in the analysis. Each study assessed dry eye symptoms using OSDI and also assessed corneal fluorescein staining in five corneal zones. For each subject, the corneal zones were ranked 1–5 according to their relative staining grade, Rank-1 representing the highest grade.ResultsData from 13 studies and 368 subjects were included. The total number of zones assigned Rank-1 (worst) staining was 449 (across 264 subjects). The inferior zone had the most Rank-1 counts of all zones at 193/43%, which involved 52.5% of all subjects. The nasal zone had 77/17% involving 20.9% of subjects, followed by the temporal (69/15.5%, 18.8% subjects) and superior zones (63/14%, 17.1% subjects). The central zone had the lowest count of Rank-1 designations, at only 47/10.5%, involving 12.8% of subjects. Bayesian analysis was used to generate distributions of the credible proportions of subjects likely to present with staining in a single peripheral zone, with or without central zone staining. It illustrated that staining in a peripheral zone without central staining was more credible. The worst single zone staining was most likely to present in the inferior zone (67.9%), followed by the nasal zone (11.3%), the superior zone (9.2%), and the temporal zone (5.6%).ConclusionIn the presence of dry eye symptoms, the inferior zone typically presents the most severe grade of corneal staining, more likely without central zone staining. This knowledge is valuable when developing a strategy to treat dry eye signs, as the inferior corneal zone has the highest grade of staining thus has the potential to exhibit the greatest reduction in staining post-treatment.     

自體结膜角膜缘上皮和异體羊膜移植术治疗翼状胬肉的临床研究

目的 觀察自體结膜角膜緣上皮移植術和异體羊膜移植術治療翼狀胬肉的臨床效果。方法 對55例(73只眼)行自體結膜角膜緣上皮移植術,隨訪1-17月,平均8.9月;對35例(46只眼)行异體羊膜移植術,隨訪1-14月,平均7.7月。结果兩組病例中初發性翼狀胬肉均無復發,而復發性翼狀胬肉的復發率分别為10.53％和6.67％,兩者無顯著性差异(P>0.05),但后者術后反應輕、上皮恢復快。结論 自體結膜角膜緣上皮移植術和异體羊膜移植術均是治療翼狀胬肉的良好方法,以后者為佳,治療翼狀胬肉的關鍵在于初發性手術方式的選擇。     

自体角膜缘上皮移植治疗翼状胬肉

目的观察自体角膜缘上皮移植术治疗翼状胬肉的疗效。方法采用自体角膜缘上皮移植术对６８例（７６只眼）初发和复发性翼状胬肉患者进行治疗,术后随访６～１８个月。结果６８例（７６只眼）中,５６例（６２只眼）上皮愈合稳定,角膜恢复正常光滑、透明,无异常翼状胬肉样组织生长。１２例（１４只眼）失访。结论自体角膜缘上皮移植可为病变区角膜及结膜提供新的干细胞来源,是治疗初发性和复发性翼状胬肉的理想方法。