[1]王群,姜严明,赵杰,等.血管内皮生长因子靶向抗体对大鼠角膜碱烧伤后新生血管抑制作用的研究[J].眼科新进展,2017,37(11):1010-1014.[doi:10.13389/j.cnki.rao.2017.0256]
 WANG Qun,JIANG Yan-Ming,ZHAO Jie,et al.Inhibitory effects of anti-vascular endothelial growth factor (VEGF) antibody MIL60 on alkali-induced corneal angiogenesis in rats[J].Recent Advances in Ophthalmology,2017,37(11):1010-1014.[doi:10.13389/j.cnki.rao.2017.0256]
点击复制

血管内皮生长因子靶向抗体对大鼠角膜碱烧伤后新生血管抑制作用的研究/HTML
分享到:

《眼科新进展》[ISSN:1003-5141/CN:41-1105/R]

卷:
37卷
期数:
2017年11期
页码:
1010-1014
栏目:
实验研究
出版日期:
2017-11-05

文章信息/Info

Title:
Inhibitory effects of anti-vascular endothelial growth factor (VEGF) antibody MIL60 on alkali-induced corneal angiogenesis in rats
作者:
王群姜严明赵杰侯宝杰吕明黄一飞
100039 北京市,武警总医院眼科(王群,赵杰,侯宝杰);100088 北京市,火箭军总医院眼科(姜严明);100086 北京市,军事医学科学院(吕明);100053 北京市,解放军总医院眼科(黄一飞)
Author(s):
WANG QunJIANG Yan-MingZHAO JieHOU Bao-JieLV MingHUANG Yi-Fei
Department of Ophthalmology,General Hospital of CAPF(WANG Qun,ZHAO Jie,HOU Bao-Jie),Beijing 100039,China;Department of Ophthalmology,General Hospital of PLA Rocket Force(JIANG Yan-Ming),Beijing 100088,China;Academy of Military Medical Sciences(LV Ming),Beijing 100086,China;Department of Ophthalmology,General Hospital of PLA(HUANG Yi-Fei),Beijing 100053,China
关键词:
血管内皮生长因子MIL60角膜新生血管碱烧伤
Keywords:
vascular endothelial growth factorMIL60corneal neovascularizationalkali cauterization
分类号:
R772.2
DOI:
10.13389/j.cnki.rao.2017.0256
文献标志码:
A
摘要:
目的 通过对角膜碱烧伤大鼠模型结膜下注射VEGF靶向抗体MIL60,观察其对角膜新生血管(corneal neovascularization,CoNV)生长的影响,初步探讨MIL60抑制大鼠CoNV生长的基本作用机制。方法 建立碱烧伤诱导的SD大鼠CoNV模型(右眼造模),根据碱烧伤后第1天结膜下注射的药物不同将72只大鼠随机分为:25 mg·mL-1 MIL60组、地塞米松组、MIL60溶剂组和NaCl组。观察并记录CoNV生长情况及角膜的形态变化,通过软件分析CoNV的长度及累及面积。碱烧伤后第3天、第7天、第14天、第21天和第28天分别处死动物,取角膜组织行HE染色和免疫组织化学染色,同时检测角膜中血管内皮生长因子(vascular endothelial growth factor,VEGF)、VEGF受体-1(VEGF receptor-1,VEGFR-1)、VEGFR-2和基质金属蛋白酶-9 (matrix metallopeptidase-9,MMP-9)蛋白的表达。结果 在各个时间点,与MIL60溶剂组和NaCl组比较,地塞米松组、25 mg·mL-1 MIL60组CoNV面积和长度显著减少,差异均具有统计学意义(均为P<0.01);25 mg·mL-1 MIL60组的CoNV长度和面积与地塞米松组相当(均为P>0.05)。同时,MIL60还能有效降低角膜组织中VEGF、VEGFR-1、VEGFR-2以及MMP-9蛋白的表达。结论 MIL60能显著抑制角膜碱烧伤后CoNV的生长,并且还能减轻碱烧伤引起的炎症反应。
Abstract:
Objective To investigate the efficacy of an anti-vascular endothelial growth factor (VEGF) antibody,MIL60,in inhibiting corneal neovascularization (CoNV) formation in a rat model of alkali cauterization and its involved mechanisms.Methods Rat CoNV model induced by alkali burn was founded in the right eyes,and then 72 cases were randomly divided into four groups according to the subconjunctival administration of medicine next day after the successful establishment of this model:25 mg·mL-1 MIL60 group,dexamethasone group,MIL60 solvent group and NaCl group.Then CoNV was observed for recording the its length and the involved area using digital photograph.Next the rats were sacrificed on day 7,14,21 and 28,followed by the collection of rats’ cornea for HE and immunohistochemical staining to analyze the protein expression of VEGF,VEGF receptor-1 (VEGFR-1),VEGFR -2 and matrix metallopeptidase-9 (MMP-9).Results At each time point,the area and length of CoNV in the 25 mg·mL-1 MIL60 and dexamethasone group were significantly less than those in the MIL60 solvent and NaCl group,and the differences were statistically significant (all P<0.01),and 25 mg·mL-1 MIL60 group had the similar CoNV area and length with the dexamethasone group (all P>0.05).Moreover,HE and immunohistochemical staining showed that MIL60 could inhibit the protein expression of VEGF,VEGFR-1,VEGFR-2 and MMP-9,which could explain its effective anti-angiogenic activity.Conclusion Subconjunctival administration of MIL60 can significantly inhibit corneal neovascularization formation and alleviate the inflammation in rats suffered from alkali burn.

参考文献/References:

[1] PHILIP PW,SPEICHER L,HUMPEL C.Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas[J].Invest Ophthamlol Vis Sci,2004,41(9):2514-2522.
[2] 周兰新,李立,鄢秀菊.奥曲肽抑制角膜新生血管形成的实验研究[J].眼科新进展,2006,26(9):674-677.
ZHOU LX,LI L,YAN XJ.Octreotide inhibits corneal neovascularization induced by alkali burn[J].Rec Adv Ophthalmol,2006,26(9):674-677.
[3] 李宇,邓应平,张明,唐静,孟丹.KH902抑制大鼠角膜新生血管的实验研究[J].四川大学学报(医学版),2013,44(1):64-67.
LI Y,DENG YP,ZHANG M,TANG J,MENG D.Experimental research of KH902 inhibition of corneal neovascularization in rats[J].J Sichuan Univ(Med Sci Edit),2013,44(1):64-67.
[4] YANG J,WANG Q,QIAO C,LIN Z,LI X,HUANG Y,et al.Potent anti-angiogenesis and anti-tumor activity of a novel human anti-VEGF antibody,MIL60[J].Cell Mol Immunol,2014,11(3):285-293.
[5] LU P,LI L,LIU G,VAN ROOIJEN N,MUKAIDA N,ZHANG X.Opposite roles of CCR2 and CX3CR1 macrophages in alkali-induced corneal neovascularization[J].Cornea,2009,28(5):562-569.
[6] SIMPSON DA,MURPHY GM,BHADURI T,GARDINER TA,ARCHER DB,STITT AW.Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia[J].Biochem Biophya Res Commun,1999,262(2):333-340.
[7] ZHANG SX,MA JX.Ocular neovascularization:Implication of endogenous angiogenic inhibitors and potential therapy[J].Prog Retin Eye Res,2007,26(1):1-37.
[8] DETAMR M.Molecular regulation of angiogenesis in the skin[J].Invest Dermatol,1996,106:207-208.
[9] ORMEROD LD,ABELSON MB,KENYON KR.Standard models of corneal injury using alkali-immersed filter discs[J].Invest Ophthalmol Vis Sci,1898,20(10):2148-2153.
[10] FERRARA N,GERBER HP,LECOUTER J.The biology of VEGF and its receptors[J].Nat Med,2003,9(6):669-676.
[11] KAPPAS NC,ZENG G,CHAPPELL JC,KEARNEY JB,HAZARIKA S,KALLIANOS KG,et al.The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching[J].J Cell Biol,2008,181(5):847-858.
[12] BANERJEE S,MEHTA S,HAQUE I,SENGUPTA K,DHAR K,KAMBHAMPATI S,et al.VEGF-A165 induces human aortic smooth muscle cell migration by activating neuropilin-1-VEGFR1-PI3K axis[J].Biochemistry,2008,47(11):3345-3351.
[13] LEE HK,CHAUHAN SK,KAY E,DANA R.Flt-1 regulates vascular endothelial cell migration via a protein tyrosine kinase-7-dependent pathway[J].Blood,2011,117(21):5762-5771.
[14] KANNO S,ODA N,ABE M,TERAI Y,ITO M,SHITARA K,et al.Roles of two VEGF receptors,Flt-1 and KDR,in the signal transduction of VEGF effects in human vascular endothelial cells[J].Oncogene,2000,19(12):2138-2146.
[15] BREKKEN RA,OVERHOLSER JP,STASTNY VA,WALTENBERGER J,MINNA JD,THORPE PE.Selective inhibition of vascular endothelial growth factor(VEGF) receptor-2(KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice[J].Cancer Res,2000,60:5117-5124.
[16] ZHANG EP,MULLER A,SCHULTE F,KNIG MS,SACK F,JUNGHANS C,et al.Minimizing side effects of ballistic gene transfer into the murine corneal epithelium[J].Graefes Arch Clin Exp Ophthalmol,2002,240:114-119.
[17] 于晓晖,郝敏,康凤英.基质金属蛋白酶抑制剂在角膜疾病中的应用[J].国际眼科纵览,2006,30(1):54-57.
YU XH,HAO M,KANG FY.The application of matrix metalloproteinase inhibitors in the corneal diseases[J].Int Rev Ophthalmol,2006,30(1):54-57.
[18] CEJKA C,HOLAN V,TROSAN P,ZAJICOVA A,JAVORKOVA E,CEJKOVA J.The favorable effect of mesenchymal stem cell treatment on the antioxidant protective mechanism in the corneal epithelium and renewal of corneal optical properties changed after alkali burns[J].Oxid Med Cell Longev,2016,2016:5843809.
[19] DERYUGINA EI.Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis[J].Cancer Res,2002,62(2):580-588.
[20] BELOTTI D,PAGANONI P,MANENTI L.Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells:implications for ascites formation[J].Cancer Res,2003,63(17):5224-5229.
[21] BERGERS G,BREKKEN R,MCMAHON G,VU TH,ITOH T,TAMAKI K,et al.Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis[J].Nat Cell Biol,2000,2(10):737-744.
[22] MOHAN R,SIVAK J,ASHTON P,RUSSO LA,PHAM BQ,KASAHARA N,et al.Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2,including expression of matrix metalloproteinase gelatinase B[J].J Biol Chem,2000,275(14):10405-10412.

相似文献/References:

[1]程文武 江萍 席祖莲 张汉武 訾世莉 聂军 董彩虹.蛹虫草提取物抑制大鼠角膜新生血管的实验研究[J].眼科新进展,2012,32(5):000.
[2]于静 张明昌.苦参碱对大鼠角膜新生血管的抑制作用[J].眼科新进展,2012,32(6):000.
[3]吴正正 严京 接传红 高健生 陈皆春 宋剑涛.密蒙花方对缺氧状态下脐静脉血管内皮细胞 VEGF-VEGFR 信号转导通路的影响[J].眼科新进展,2012,32(7):000.
[4]庞霞 曲蕴慧 马跃伟 张效房 董敬民 高冬玲.去整合素金属蛋白酶9和血管内皮生长因子蛋白在眼部恶性黑色素瘤中的表达[J].眼科新进展,2012,32(7):000.
[5]李艳 李筱荣 袁佳琴 潘斌.糖尿病大鼠视网膜中VEGF、PEDF的表达与血-视网膜屏障损伤[J].眼科新进展,2013,33(1):000.
[6]许琴 黄亮 林素香 郑水华 肖煜晨 王雅丽.激光诱导小鼠脉络膜新生血管中膜攻击物与血管生长因子的表达[J].眼科新进展,2013,33(8):000.
[7]李小璐 马雅玲.糖尿病视网膜病变大鼠视网膜VEGF和PEDF的动态表达[J].眼科新进展,2013,33(9):000.
[8]曾莉 常以力 邵毅.血管内皮生长因子反义寡脱氧核苷酸联合血管生成素-1对糖尿病视网膜病变大鼠视网膜血管渗漏及新生血管生成的影响[J].眼科新进展,2012,32(10):000.
[9]兰兰 惠延年 曾光伟.血管生成素-1对糖尿病大鼠视网膜微血管病变、基质金属蛋白酶和血管内皮生长因子的抑制作用[J].眼科新进展,2012,32(10):000.
[10]谢明捷 吕红彬 何跃 赵春会.炎症因子与糖尿病视网膜病变相关性研究进展[J].眼科新进展,2012,32(10):000.

备注/Memo

备注/Memo:
武警总医院院内课题(编号:wz2015011)
更新日期/Last Update: 2017-11-01