丝裂霉素抑制兔角膜新生血管的实验研究
摘要
目的:通过实验的方法探讨丝裂霉素抑制碱烧伤后兔角膜新生血管的作用,探讨了角膜新生血管增生与炎细胞浸润、血管内皮生长因子的表达、CD34的表达之间的关系,同时对丝裂霉素的角膜毒副作用进行对比研究。
方法:24只新西兰大白兔随机分成二组,每组12只,检查排除眼部疾病后,双眼用碱烧伤的方法制成角膜新生血管模型,一组右眼(A组)给予生理盐水点眼,4次/日,一组左眼(B组)分别于碱烧伤后第1、10天给予丝裂霉素结膜下注射各一次,二组右眼(C组)给予普南扑灵眼液点眼,4次/日,二组左眼(D组)给予地塞米松眼液点眼,4次/日,每日抗生素眼药点眼预防感染,隔日观测角膜水肿、角膜融解及角膜新生血管生长情况,于7天、14天每组各取半数家兔耳缘静脉空气栓塞法处死,取角膜组织行HE染色及VEGF、CD34免疫组化检测,高倍镜下计数新生血管及多形核白细胞。
结果:碱烧伤后24小时内角膜缘血管扩张、充血,3天后角膜缘有血管芽长入,角膜水肿明显,10天后角膜新生血管生长进入高峰,部分出现角膜溃疡,A组有2例出现假性前房积脓,此后炎症反应逐渐减轻,角膜上皮开始生长,多数角膜溃疡愈合,前房积脓吸收。统计学分析结果,丝裂霉素对角膜新生血管有明显的抑制作用(A组与B组相比,新生血管的四种检测结果对比统计分析P值分别为0.000,0.005,0.000,0.000,差异有统计学意义),丝裂霉素抑制角膜新生血管的作用比地塞米松作用稍强(B组与D组相比,新生血管的四种检测结果对比统计分析P值分别为0.078,0.291,0.193,0.046差异无统计学意义),从药物对角膜的毒副作用来看,丝裂霉素后期反应较其轻(B组与D组相比):两个时间组对比,角膜水肿P值为0.000;角膜融解P值为P7=0.000,P14=0.136;HE下多形核白细胞计数:P7=0.034,P14=0.000,差异有统计学意义。
结论:非细胞毒浓度丝裂霉素结膜下注射对碱烧伤后兔角膜新生血管具有明显的抑制作用,各组新生血管增生的活体检测、镜下测量微血管数与VEGF和CD34的含量是同步变化的,丝裂霉素的角膜毒副作用明显低于对照组,与普南扑灵、地塞米松相比无明显差异。
Objective: Research the effect of mitomycin-C on inhibiting rabbit's corneal neovascularization after alkali burning and to evaluate its toxicant side effect on cornea with control and the relationship between proliferation of corneal neovascularization and inflammatory cell inflitration and VEGF and CD34 by experimental method.
Methods: 24 healthy rabbits are take into this experiments that have eyes diseases are excluded, and they are divided into two groups randomly. There are 12 rabbits in each group. The corneal neovascularization was induced on both eyes by alkali burn in 24 white rabbits. 0.9% Sodium chloride was dropped four times daily in group A, mitomycin-C was injected subconjunctival tissues in group B, pranoprofen was dropped four times daily in group C, dexamethasone was dropped four times daily in group D. The development of cornea edema dilapsus and the growth of neovascularization were observed in every other day, six rabbits in each group were put to death by injecting air in the vein of it’s ear in seventh and fourteenth day, the cornea tissues were accounted by immunhistochemical analysis of Vascular Endothelial Growth Factor and CD34, hematoxylin and eosin stain under high power lens.
Results: The vascular in corneal limbus become telangiectatic, and congest 24h after alkali burning. Vascular grow into cornea in 3 days, corneal neovascularization grow fast in 10 days. Cornea edema is obviously in all cases early, there are 2 cases were fond partly corneal ulcer in group A. corneal epithelium cells begin to grow several days later. We can find the corneal neovascularization were inhibited strongly in group B than it in group A,C and D, the value P were 0.000, 0.005, 0.000, 0.000 in which group B correspond to group A, the inhibit effect were stronger than dexamethasone , the value P were 0.078, 0.291, 0.193and 0.046 in which group B correspond to group D, and the immunreactivity were slower and fewer than group D. Between seventh and fourteenth day, the value P of cornea edema was 0.000,the cornea dilapsus were P7=0.000,P14=0.136,the polymorphonuclear leukocyte under hematoxylin and eosin stain were P7=0.034,P14=0.000.
Conclusions: Non-toxic mitomycin-C which inject subconjunctiva has a strong effect on inhibiting corneal neovascularization after alkali burning. Proliferation of corneal neovascularization checked by biopsy and microvessel density under high power lens has a strong relationship with VEGF and CD34 in each group. Topical application of mitomycin-C has significant effects on the inhibition of corneal neovascularization, and it’s toxicant side effect on cornea have no significant difference correspond to dexamethasone.
方法:24只新西兰大白兔随机分成二组,每组12只,检查排除眼部疾病后,双眼用碱烧伤的方法制成角膜新生血管模型,一组右眼(A组)给予生理盐水点眼,4次/日,一组左眼(B组)分别于碱烧伤后第1、10天给予丝裂霉素结膜下注射各一次,二组右眼(C组)给予普南扑灵眼液点眼,4次/日,二组左眼(D组)给予地塞米松眼液点眼,4次/日,每日抗生素眼药点眼预防感染,隔日观测角膜水肿、角膜融解及角膜新生血管生长情况,于7天、14天每组各取半数家兔耳缘静脉空气栓塞法处死,取角膜组织行HE染色及VEGF、CD34免疫组化检测,高倍镜下计数新生血管及多形核白细胞。
结果:碱烧伤后24小时内角膜缘血管扩张、充血,3天后角膜缘有血管芽长入,角膜水肿明显,10天后角膜新生血管生长进入高峰,部分出现角膜溃疡,A组有2例出现假性前房积脓,此后炎症反应逐渐减轻,角膜上皮开始生长,多数角膜溃疡愈合,前房积脓吸收。统计学分析结果,丝裂霉素对角膜新生血管有明显的抑制作用(A组与B组相比,新生血管的四种检测结果对比统计分析P值分别为0.000,0.005,0.000,0.000,差异有统计学意义),丝裂霉素抑制角膜新生血管的作用比地塞米松作用稍强(B组与D组相比,新生血管的四种检测结果对比统计分析P值分别为0.078,0.291,0.193,0.046差异无统计学意义),从药物对角膜的毒副作用来看,丝裂霉素后期反应较其轻(B组与D组相比):两个时间组对比,角膜水肿P值为0.000;角膜融解P值为P7=0.000,P14=0.136;HE下多形核白细胞计数:P7=0.034,P14=0.000,差异有统计学意义。
结论:非细胞毒浓度丝裂霉素结膜下注射对碱烧伤后兔角膜新生血管具有明显的抑制作用,各组新生血管增生的活体检测、镜下测量微血管数与VEGF和CD34的含量是同步变化的,丝裂霉素的角膜毒副作用明显低于对照组,与普南扑灵、地塞米松相比无明显差异。
Objective: Research the effect of mitomycin-C on inhibiting rabbit's corneal neovascularization after alkali burning and to evaluate its toxicant side effect on cornea with control and the relationship between proliferation of corneal neovascularization and inflammatory cell inflitration and VEGF and CD34 by experimental method.
Methods: 24 healthy rabbits are take into this experiments that have eyes diseases are excluded, and they are divided into two groups randomly. There are 12 rabbits in each group. The corneal neovascularization was induced on both eyes by alkali burn in 24 white rabbits. 0.9% Sodium chloride was dropped four times daily in group A, mitomycin-C was injected subconjunctival tissues in group B, pranoprofen was dropped four times daily in group C, dexamethasone was dropped four times daily in group D. The development of cornea edema dilapsus and the growth of neovascularization were observed in every other day, six rabbits in each group were put to death by injecting air in the vein of it’s ear in seventh and fourteenth day, the cornea tissues were accounted by immunhistochemical analysis of Vascular Endothelial Growth Factor and CD34, hematoxylin and eosin stain under high power lens.
Results: The vascular in corneal limbus become telangiectatic, and congest 24h after alkali burning. Vascular grow into cornea in 3 days, corneal neovascularization grow fast in 10 days. Cornea edema is obviously in all cases early, there are 2 cases were fond partly corneal ulcer in group A. corneal epithelium cells begin to grow several days later. We can find the corneal neovascularization were inhibited strongly in group B than it in group A,C and D, the value P were 0.000, 0.005, 0.000, 0.000 in which group B correspond to group A, the inhibit effect were stronger than dexamethasone , the value P were 0.078, 0.291, 0.193and 0.046 in which group B correspond to group D, and the immunreactivity were slower and fewer than group D. Between seventh and fourteenth day, the value P of cornea edema was 0.000,the cornea dilapsus were P7=0.000,P14=0.136,the polymorphonuclear leukocyte under hematoxylin and eosin stain were P7=0.034,P14=0.000.
Conclusions: Non-toxic mitomycin-C which inject subconjunctiva has a strong effect on inhibiting corneal neovascularization after alkali burning. Proliferation of corneal neovascularization checked by biopsy and microvessel density under high power lens has a strong relationship with VEGF and CD34 in each group. Topical application of mitomycin-C has significant effects on the inhibition of corneal neovascularization, and it’s toxicant side effect on cornea have no significant difference correspond to dexamethasone.
引文
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[2] Yuko Gobto, Akira Obana, Masakazu Kanai, et al.Photodynamic Therapy for Corneal Neovascularization Using Topically Administered ATX-S10(Na). Ophthalmic Surg Lasers, 2000, 31(1):55-60.
[3]Demir T, Celiker UO, Kukner A, et al. Effect of octreotide on experimental corneal neovascularization. Acta Ophthalmol Scand, 1999, 77:386-390.
[4]Kenyon BM, Browne F, D Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res, 1997, 64:971-978.
[5] Eric D, Donnenfeld, Henry D, Perry, Avi Wallerstein, et al. Subconjunctival Mitomycin C for the Treatment of Ocular Cicatricial Pemphigoid. Ophthalmology, 1999, 106(1):72-78.
[6] Yihai Cao, Philip Linden, Jacob Farnebo, et al. Vascular endothelial growth factor C induces angiogenesis in vivo. Medical Sciences, 1998, 95:14389-14394.
[7]Burns PA, Wilson DJ. Angiogenesis mediated by metabolites is dependent on vascular endothelial growth factor (VEGF). Angiogenesis, 2003, 6(1):73-77.
[8] Claus Cursiefen, Lu Chen, Leonardo P, Borges, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. Clin Invest, 2004, 113(7):1040-1050.
[9]Simpaon DA, Murphy GM, Bhaduri T, et al. Biochem Biophya Res Commun, 1999,262:333.
[10]Rupal H. T, Liliana W, David J.A, et al. Part I: Toxicity to corneal endothelial cells in a rabbit model. J Cataract Refract Surg, 2003, 29:550-555.
[11] Gross RL. Collagen type Ⅰand Ⅲ synthesis by Tenon’s capsule fibroblasts in culture: Individual patient characteristics and response to mitomycin C, 5-fluorouracil, and ascorbic acid. Trans Am Ophthalmol Soc, 1999, 97:513-543.
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