rAAV介导HSV-tk/GCV系统对兔后囊膜混浊的抑制及眼前段组织学影响的研究
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摘要
目的研究重组腺相关病毒(recombinant adeno-associated virus,rAAV)介导的单纯疱疹病毒胸苷激酶(herpes simplex virus thymidinekinase,HSV-tk)/丙氧鸟苷(ganciclovir,GCV)系统对兔眼白内障术后后囊膜混浊(posterior capsule opacification,PCO)的抑制作用及对眼前段组织的组织学影响。
方法
1.将24只家兔均行右眼晶状体超声乳化吸除术,术毕随机均分成4组,每组6只。1、2组囊袋内注入0.1ml平衡盐溶液(balenced saltsolution,BSS),3、4组囊袋内注入0.1ml携带有HSV—tk的rAAV载体。术后24h第1、3组前房内注入0.1mlBSS,2、4组注入0.1mlGCV,每天1次,连续3天。术后术眼行裂隙灯检查。
2.术后第28天行兔眼角膜内皮显微镜检查、行免疫组化染色检测后囊膜增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)阳性表达及眼前段组织学检查。
结果
1.裂隙灯检查:第28天第4组PCO明显轻于其他3组(P＜0.05),统计学分析差异有显著性,其余3组差异无显著性(P＞0.05)。
2.组织学检查:各组角膜及虹膜均无明显炎症反应与组织损害第4组晶状体上皮细胞增殖明显少于其他3组。
3.角膜内皮显微镜检查结果示内皮细胞密度、细胞面积及变异系数各组对比差异无显著性(P＞0.05)。
4.PCNA检查结果可见,第4组PCNA阳性表达少于其他3组,测积分光密度并统计学分行析差异有显著性(P＜0.05)。
结论重组腺相关病毒载体介导HSV—tk/GCV系统对兔眼PCO有明显的抑制作用,且对眼前段组织无组织损害。
Objiective To investigate the inhibiting effect of adeno-associated virus-mediated herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV)system on posterior capsule opacification(PCO) in rabbits and the toxicity in eye anterior segment.
Methods
1. 24 rabbits(24 eyes) were randomly divided into 4 groups .All rabbits were given phacoemulsification in each right eye.During operation,the group 1 and group 2 were injected 0.1ml Balenced salt solution(BSS) in the capsular bag,and the group 3 and group 4 were injected 0.1ml adeno-associated virus-mediated HSV-tk in the capsular bag . 24 hours later ,0.1ml BSS was injeceted in the ocular anterior chamber of group 1 and 3 ,and 0.1ml GCV was injected in the ocular anterior bag of group 2 and 4,once a day,for three days. In the four-week follow-up after operation,every right eye undertook the slit-lamp examination.
2. Every right eye undertook corneal endothelium microscope examination in the 28 day after operation.Immunohistochemical staining was used to detected proliferating cell nuclear antigen(PCNA) masculine expression in posterior capsule and histological Influence of anterior segment of eye.
Resoults
1. slit-lamp examination:The PCO in the eyes of group 4 was markedly lower than that of other three groups(P<0.05). No statistical difference was found among the other three groups.
2.Histological examination:There was no obviously inflammatory reaction and histological damage to the cornea and iris in every group.Proliferation of the lens epithelial cells in group 4 was significantly lower than that of other three groups.
3.There was no statistically difference among each group on corneal endothelial cell density、mean cell area and coefficient of variation .
4.PCNA masculine expression in posterior capsule in group 4 was significantly lower than that of other three groups. Conclusion adeno-associated virus-mediated HSV-tk/GCV system can effectively prevent of PCO.And there was no histological damage to the anterior segment of eye.
方法
1.将24只家兔均行右眼晶状体超声乳化吸除术,术毕随机均分成4组,每组6只。1、2组囊袋内注入0.1ml平衡盐溶液(balenced saltsolution,BSS),3、4组囊袋内注入0.1ml携带有HSV—tk的rAAV载体。术后24h第1、3组前房内注入0.1mlBSS,2、4组注入0.1mlGCV,每天1次,连续3天。术后术眼行裂隙灯检查。
2.术后第28天行兔眼角膜内皮显微镜检查、行免疫组化染色检测后囊膜增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)阳性表达及眼前段组织学检查。
结果
1.裂隙灯检查:第28天第4组PCO明显轻于其他3组(P＜0.05),统计学分析差异有显著性,其余3组差异无显著性(P＞0.05)。
2.组织学检查:各组角膜及虹膜均无明显炎症反应与组织损害第4组晶状体上皮细胞增殖明显少于其他3组。
3.角膜内皮显微镜检查结果示内皮细胞密度、细胞面积及变异系数各组对比差异无显著性(P＞0.05)。
4.PCNA检查结果可见,第4组PCNA阳性表达少于其他3组,测积分光密度并统计学分行析差异有显著性(P＜0.05)。
结论重组腺相关病毒载体介导HSV—tk/GCV系统对兔眼PCO有明显的抑制作用,且对眼前段组织无组织损害。
Objiective To investigate the inhibiting effect of adeno-associated virus-mediated herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV)system on posterior capsule opacification(PCO) in rabbits and the toxicity in eye anterior segment.
Methods
1. 24 rabbits(24 eyes) were randomly divided into 4 groups .All rabbits were given phacoemulsification in each right eye.During operation,the group 1 and group 2 were injected 0.1ml Balenced salt solution(BSS) in the capsular bag,and the group 3 and group 4 were injected 0.1ml adeno-associated virus-mediated HSV-tk in the capsular bag . 24 hours later ,0.1ml BSS was injeceted in the ocular anterior chamber of group 1 and 3 ,and 0.1ml GCV was injected in the ocular anterior bag of group 2 and 4,once a day,for three days. In the four-week follow-up after operation,every right eye undertook the slit-lamp examination.
2. Every right eye undertook corneal endothelium microscope examination in the 28 day after operation.Immunohistochemical staining was used to detected proliferating cell nuclear antigen(PCNA) masculine expression in posterior capsule and histological Influence of anterior segment of eye.
Resoults
1. slit-lamp examination:The PCO in the eyes of group 4 was markedly lower than that of other three groups(P<0.05). No statistical difference was found among the other three groups.
2.Histological examination:There was no obviously inflammatory reaction and histological damage to the cornea and iris in every group.Proliferation of the lens epithelial cells in group 4 was significantly lower than that of other three groups.
3.There was no statistically difference among each group on corneal endothelial cell density、mean cell area and coefficient of variation .
4.PCNA masculine expression in posterior capsule in group 4 was significantly lower than that of other three groups. Conclusion adeno-associated virus-mediated HSV-tk/GCV system can effectively prevent of PCO.And there was no histological damage to the anterior segment of eye.
引文
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[2]丁芝祥,谭浅,刘双珍,等.重组增强型绿色荧光蛋白腺相关病毒转染兔晶状体上皮细胞的研究.眼科新进展,2006,26(12):889-892
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[7]Ibaraki N,Li RL,Venkat N.Effect of Growth Factors on Proliferation and Differentiation in Human Lens Epithelial Cells in Early Subculture[J].Invest Ophthalmol Vis Sci,1995,36(11):2304-2312
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[16]Joyce NC,Meklir B,Joyce SJ,et al.Cell cycle protein expression and proliferative status in human corneal cells[J].Invest Ophthalmol Vis Sci,1996,37:654-655
[17]Rossi C,Morita H,Sormunen R,et al.Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney[J].EMBO J,2003,22(2):236-245
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[23]Takasaki Y,Kaneda K,Takeuchi K,et al.Analysis of the structure of proteasome roliferating cell nuclear antigen(PCNA)multiprotein complex and its autoimmune response in lupus patients[J].Ann N Y AcadSci,2003,987:316-318
[24]Sporbert A,Domaing P,Leonhardt H,et al.PCNA acts as a stationary loading platform for transiently interacting okazaki fragment maturation proteins[J]. Oxford University Press,2005,33(11):3521-3528
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[26]Xu J,Morris GF.P53 - mediated regulation of proliferating cell nuclear antigen expression in cells exposed to inizing radiation[J]Mol Cell Bio,1999,19(1):12.
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[2]丁芝祥,谭浅,刘双珍,等.重组增强型绿色荧光蛋白腺相关病毒转染兔晶状体上皮细胞的研究.眼科新进展,2006,26(12):889-892
[3]Couderc B.C.,De Neuville S.,Douin-Echinard V.,et al.retrovirus-mediated transfer of a suicide gene into lens epithelial cells in vitro and in an experimental model of posterior capsule opacification,Current Eye Research.1999;19(6):472-482
[4]Malecaze F,Couderc B,Neuville DN.adenovirus-mediated suicide gene transduction:feasibility in lens epithelium and in prevention of posterior capsule opacification in rabbits,Hum.Gene Ther.1999;18(14):2365-2372
[5]Saxby LA.Secondary cataract In:Yanoff M,Duker JS.Ophthalmolgy[M].3rd ed.London:Mosby,2001:1-41
[6]Apple DJ,Solomon KD,Tetz MR,et al.Posterior capsule opacification[J].Surv Ophthalmolol,1992,37,(2):73-116
[7]Ibaraki N,Li RL,Venkat N.Effect of Growth Factors on Proliferation and Differentiation in Human Lens Epithelial Cells in Early Subculture[J].Invest Ophthalmol Vis Sci,1995,36(11):2304-2312
[8]Martin P.Wound healing-aiming for perfect skin regeneration[J].Science,1997,276(5309):75-81
[9]Worm stone IM,Tam iya S,Anderson I,et al,TGFb2-induced matrix modification and cell transdifferentiation in the human lens capsular bag[J].Invest Ophthalmol Vis Sci.2002,43(7):2301-2308
[10]Saika S.Relationship between posterior capsule opacification and intraocular lens biocompatibility[J].Prog Retin Eye Res,2004,23(3):283-305
[11]Hay ED.An overview of epithelio-mesenchymal transformation.Acta Anat(Basel),1995,154(1):8-20
[12]Mizukami H,Young NS,Brown KE.Adeno-associated virus type 2 binds to a 150-kilodalton cell membrance glycoprotein[J].Virology,1996,217(1):124-130
[13]Summerford C,Samuski RJ.Membrance associated heparin sulfate proteoglycan is a receptor for high titer recombinant adeno-associated vires type 2 virions[J].J Virol,1998,72(2):1438-1445
[14]Qing K,Mah C,Hansen J,et al.Human fibroblast growth factor receptor 1 is a coreceptor for infection by adeno-associated virus 2[J].Nat Med,1999,5(1):71-77
[15]Summerford C,Bartlett JS,Samuski RJ.αV β5 integrin:A coreceptor for adeno-associated vires type 2 infection[J].Nat Med,1999,5(1)78-82
[16]Joyce NC,Meklir B,Joyce SJ,et al.Cell cycle protein expression and proliferative status in human corneal cells[J].Invest Ophthalmol Vis Sci,1996,37:654-655
[17]Rossi C,Morita H,Sormunen R,et al.Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney[J].EMBO J,2003,22(2):236-245
[18]Huang TX,Feldmeier M,Shui YB,et al.Evaluation of fibroblast growth factor signaling during lens fiber cell differentiation[J].Invest Ophthalmol Vis Sci,2003,44:680-690
[19]Kolberg R.The bystander effect in gene therapy:great,but how does it work?J NIH.Res,1944,6:62-64
[20]Samejima Y,Meruelo D."Bystander killing" induces apoptosis and is inhibited by forskolin,Gene Ther,1995,2:50-58
[21]Lal S,Lauer UM,Niethammer D,et al.Suicide genes:past,present and future perspectives[J].Immunology Today,2001,21(1):48-54.
[22]翁景宁,张惠蓉.Bcl-2基因和增殖细胞核抗原在人晶状体上皮细胞中的表达.中华眼科杂志,2001;37(3):197-199
[23]Takasaki Y,Kaneda K,Takeuchi K,et al.Analysis of the structure of proteasome roliferating cell nuclear antigen(PCNA)multiprotein complex and its autoimmune response in lupus patients[J].Ann N Y AcadSci,2003,987:316-318
[24]Sporbert A,Domaing P,Leonhardt H,et al.PCNA acts as a stationary loading platform for transiently interacting okazaki fragment maturation proteins[J]. Oxford University Press,2005,33(11):3521-3528
[25]Toueille M,Saint-Jean B,Castroviejo M.The elongation factor 1A:A novel regulator in the DNA replication/repair protein network in wheat cells?[J].Plant Phusiol Biochem,2007,45(2):113-118
[26]Xu J,Morris GF.P53 - mediated regulation of proliferating cell nuclear antigen expression in cells exposed to inizing radiation[J]Mol Cell Bio,1999,19(1):12.
[27]Kelman Z,Hurwitz J.Protein-PCNA interactions:a DNA-scanning mechanism.Trends in Biochemical Sciences,1998;23(7):236-238
[28]周炼红,刑怡桥,叶美洪,汪道文.重组腺相关病毒介导的报告基因在角膜内皮细胞中的表达.眼科研究,2006,24(2):169-17
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