Bevacizumab对BN大鼠脉络膜新生血管生成及发育影响的实验研究
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摘要
脉络膜新生血管是导致渗出型老年黄斑变性、病理性近视等多种疾病视力严重下降的重要原因。目前已有临床研究显示玻璃体腔内注射VEGF-A全长抗体bevacizumab能促使多种原因导致的CNV及特发性CNV消退,黄斑水肿吸收。然而在临床应用中,大部分患者单次玻璃体腔给予bevacizumab后视力提高无法长时间保持。现有的关于bevacizumab对CNV抑制作用的在体研究由于CNV模型的缺陷,尚无法确切反应bevacizumab对CNV的疗效。因此,我们拟利用激光诱导的BN大鼠CNV模型,通过观察bevacizumab(Avastin~(TM))对其生成及发育的影响,了解bevacizumab治疗CNV的特点,期望能为更好地应用它治疗人CNV提供初步的实验依据。
第一部分半导体激光诱导BN大鼠脉络膜新生血管的研究
目的:探讨半导体激光创建棕色挪威(brown Norway,BN)大鼠脉络膜新生血管(choroidal neovascularization,CNV)模型的可行性,为CNV防治研究奠定基础。
方法:雄性BN大鼠24只,每只鼠随机取一眼作为实验眼,另一眼为对照眼。用半导体激光(波长561nm)围绕大鼠实验眼视乳头进行光凝,激光功率、光斑直径和曝光时间分别为120Mw、100μm及0.1s,每只眼光凝8点。于光凝后3、7、14、21、28、35及56d行荧光素眼底血管造影(fundus fluoresceinangiography,FFA)和吲哚菁绿血管造影(indocyanine green angiography,ICGA)检查后处死动物,摘除眼球制作标本,进行组织病理学观察。
结果:ICGA示CNV于光凝后3d生成,14d时发育完全。FFA检查显示CNV呈圆盘状高荧光,渗漏强度于14至28d保持稳定。光凝后14d,光镜下可见视网膜下CNV形成,其中央厚度14至28d维持稳定。
结论:半导体激光可以诱导BN大鼠CNV模型,成模时间短,维持时间长。
第二部分Bevacizumab对BN大鼠CNV生成及发育影响的实验研究
目的:利用激光诱导的BN大鼠CNV模型,探究玻璃体腔内注射bevacizumab对CNV发育的抑制效果。
方法:12只雄性BN大鼠,每只鼠随机取一眼作为实验眼,另一眼为对照眼。先用半导体激光光凝实验眼视网膜,然后随机分为bevacizumab组和对照组。Bevacizumab组(6眼)于光凝即时玻璃体腔内给予2μl Avastin~(TM),而对照组(6眼)给予2μl平衡液。于光凝后7d、14d和21d行FFA和ICGA观察。光凝后21d取实验眼,标本进行HE染色和VEGF免疫组化染色。
结果:光凝后7d,ICGA显示bevacizumab组和对照组均有CNV生成,但此时bevacizumab组的FFA荧光强度评分较对照组低,差异有统计学意义。然而,该组评分随后升高,但至光凝后21d仍较对照组低。光凝后21d,Bevacizumab组的CNV平均中央厚度比对照组低,差异有统计学意义,并且免疫组化显示其VEGF阴性。
结论:于BN大鼠CNV形成早期玻璃体腔内注射bevacizumab可从形态及渗漏功能两方面抑制CNV的发育。但并不能完全阻止CNV的形成,其抑制渗漏功能的效果亦无法长时间保持。因此bevacizumab联合其它治疗方法可能可以提高CNV的治疗效率。
Choroidal neovascularization(CNV) is the main reason for severe sight loss of patients with age-related macular degeneration and myopia.Several studies have showed that intravitreous bevacizumab could induce regression of CNV.However, many patients didn't have their sight improvement last long enough after intravitreously admission of bevacizumab.So far,the only study to evaluate the effects of intravitreous bevacizumab on angiogenesis was based on an rabbit model in which choroidal neovascularization was induced by VEGF165.Thus,neither the pathology of the CNV,nor the rabbit fundus vessel system shares something in common with CNV developed in human.As a result,it couldn't modeling the exact influence of intravitreous bevacizumab on angiogenesis of CNV in human eyes.The purpose of our study is to investigate the inhibitory effects of intravitreous bevacizumab on angiogenesis in a BN rat model of laser-induced choroidal neovascularization,which shares many charactors with CNV developed in human.
Part 1 Study on the experimental model of diode laser-induced choroidal neovascularization in the BN rats
Objective To evaluate the feasibility of diode laser-induced choroidal neovascularization(CNV) model in the Brown Norway rats in order to establish the foundation for the development of treatment for CNV.
Methods Experimental eyes in 24 rats were received a series of 8 diode laser(561nm) lesions per eye(120Mw,100μm,0.1s) around optic disc.Fundus fluorescein angiography(FFA) and indocyanine green angiography(ICGA) were performed,then the rats were sacrificed immediately,the eyes were enucleated and processed for histopathologic examination on days3,7,14,21,28,35,56 after laser photocoagulation..
Results ICGA showed CNV first appeared on day 3 after photocoagulation,and well-developed on day 14.On day 14,disciform leakage staining appeared in the FFA, and the score of fluorescein staining maitained stable from day 14 to 28.CNV was ascertained by light microscopy on day 14.No significant progress of the thickness of laser-induced CNV occurred from day 14 to day 28.(P＞0.05).
Conclusions The present studies demonstrated that diode laser photocoagulation could be used to produce choroidal neovascularization experimental model in the Brown Norway rat.CNV can be induced rapidly by the method,persists for a long period.
Part 2
The Effects of Intravitreous Bevacizumab on Angiogenesis in a BN Rat Model of Laser-Induced Choroidal Neovascularization.
Objective To investigate the inhibitory effects of intravitreous bevacizumab on angiogenesis in a BN rat model of laser-induced choroidal neovascularization.
Methods 12 male BN rats,who had one eye photocoagulated by diode laser to induce CNV,were randomly divided into control group and bevacizumab group.The rats in the bevacizumab group(6 eyes) received 2μl Avastin~(TM) intravitreally at the same time of photocoagulated,while the control group(6 eyes) received 2μl BSS as vehicle. Follow-up evaluations continued for 21d and included fundus fluorescein angiography(FFA) and ICGA.Enucleated eyes were processed for hematoxylin and eosin(H&E) staining and immunohistochemistry staining for VEGF.
Results ICGA showed CNV developed,similarly,both in the bevacizumab group and the control group on day 7.But the scores of fluorescein staining at that time were significantly lower in the bevacizumab group.However,the scores soon increased till day 21,but still lower than those of the control group.On day 21,the mean thickness of CNV was significantly reduced in the bevacizumab group.And the CNV in the bevacizumab group were negative for VEGF according to the result of immmuohistochemistry staining.
Conclusions Early intravitreous injection of bevacizumab can inhibit the development of CNV both in morphology and permeability in the BN rat model. However,bevacizumab could neither block the formation of CNV,nor suppress the leakage permanently.Thus,combined therapy with bevacizumab may be more potential to treat CNV effectively.
第一部分半导体激光诱导BN大鼠脉络膜新生血管的研究
目的:探讨半导体激光创建棕色挪威(brown Norway,BN)大鼠脉络膜新生血管(choroidal neovascularization,CNV)模型的可行性,为CNV防治研究奠定基础。
方法:雄性BN大鼠24只,每只鼠随机取一眼作为实验眼,另一眼为对照眼。用半导体激光(波长561nm)围绕大鼠实验眼视乳头进行光凝,激光功率、光斑直径和曝光时间分别为120Mw、100μm及0.1s,每只眼光凝8点。于光凝后3、7、14、21、28、35及56d行荧光素眼底血管造影(fundus fluoresceinangiography,FFA)和吲哚菁绿血管造影(indocyanine green angiography,ICGA)检查后处死动物,摘除眼球制作标本,进行组织病理学观察。
结果:ICGA示CNV于光凝后3d生成,14d时发育完全。FFA检查显示CNV呈圆盘状高荧光,渗漏强度于14至28d保持稳定。光凝后14d,光镜下可见视网膜下CNV形成,其中央厚度14至28d维持稳定。
结论:半导体激光可以诱导BN大鼠CNV模型,成模时间短,维持时间长。
第二部分Bevacizumab对BN大鼠CNV生成及发育影响的实验研究
目的:利用激光诱导的BN大鼠CNV模型,探究玻璃体腔内注射bevacizumab对CNV发育的抑制效果。
方法:12只雄性BN大鼠,每只鼠随机取一眼作为实验眼,另一眼为对照眼。先用半导体激光光凝实验眼视网膜,然后随机分为bevacizumab组和对照组。Bevacizumab组(6眼)于光凝即时玻璃体腔内给予2μl Avastin~(TM),而对照组(6眼)给予2μl平衡液。于光凝后7d、14d和21d行FFA和ICGA观察。光凝后21d取实验眼,标本进行HE染色和VEGF免疫组化染色。
结果:光凝后7d,ICGA显示bevacizumab组和对照组均有CNV生成,但此时bevacizumab组的FFA荧光强度评分较对照组低,差异有统计学意义。然而,该组评分随后升高,但至光凝后21d仍较对照组低。光凝后21d,Bevacizumab组的CNV平均中央厚度比对照组低,差异有统计学意义,并且免疫组化显示其VEGF阴性。
结论:于BN大鼠CNV形成早期玻璃体腔内注射bevacizumab可从形态及渗漏功能两方面抑制CNV的发育。但并不能完全阻止CNV的形成,其抑制渗漏功能的效果亦无法长时间保持。因此bevacizumab联合其它治疗方法可能可以提高CNV的治疗效率。
Choroidal neovascularization(CNV) is the main reason for severe sight loss of patients with age-related macular degeneration and myopia.Several studies have showed that intravitreous bevacizumab could induce regression of CNV.However, many patients didn't have their sight improvement last long enough after intravitreously admission of bevacizumab.So far,the only study to evaluate the effects of intravitreous bevacizumab on angiogenesis was based on an rabbit model in which choroidal neovascularization was induced by VEGF165.Thus,neither the pathology of the CNV,nor the rabbit fundus vessel system shares something in common with CNV developed in human.As a result,it couldn't modeling the exact influence of intravitreous bevacizumab on angiogenesis of CNV in human eyes.The purpose of our study is to investigate the inhibitory effects of intravitreous bevacizumab on angiogenesis in a BN rat model of laser-induced choroidal neovascularization,which shares many charactors with CNV developed in human.
Part 1 Study on the experimental model of diode laser-induced choroidal neovascularization in the BN rats
Objective To evaluate the feasibility of diode laser-induced choroidal neovascularization(CNV) model in the Brown Norway rats in order to establish the foundation for the development of treatment for CNV.
Methods Experimental eyes in 24 rats were received a series of 8 diode laser(561nm) lesions per eye(120Mw,100μm,0.1s) around optic disc.Fundus fluorescein angiography(FFA) and indocyanine green angiography(ICGA) were performed,then the rats were sacrificed immediately,the eyes were enucleated and processed for histopathologic examination on days3,7,14,21,28,35,56 after laser photocoagulation..
Results ICGA showed CNV first appeared on day 3 after photocoagulation,and well-developed on day 14.On day 14,disciform leakage staining appeared in the FFA, and the score of fluorescein staining maitained stable from day 14 to 28.CNV was ascertained by light microscopy on day 14.No significant progress of the thickness of laser-induced CNV occurred from day 14 to day 28.(P＞0.05).
Conclusions The present studies demonstrated that diode laser photocoagulation could be used to produce choroidal neovascularization experimental model in the Brown Norway rat.CNV can be induced rapidly by the method,persists for a long period.
Part 2
The Effects of Intravitreous Bevacizumab on Angiogenesis in a BN Rat Model of Laser-Induced Choroidal Neovascularization.
Objective To investigate the inhibitory effects of intravitreous bevacizumab on angiogenesis in a BN rat model of laser-induced choroidal neovascularization.
Methods 12 male BN rats,who had one eye photocoagulated by diode laser to induce CNV,were randomly divided into control group and bevacizumab group.The rats in the bevacizumab group(6 eyes) received 2μl Avastin~(TM) intravitreally at the same time of photocoagulated,while the control group(6 eyes) received 2μl BSS as vehicle. Follow-up evaluations continued for 21d and included fundus fluorescein angiography(FFA) and ICGA.Enucleated eyes were processed for hematoxylin and eosin(H&E) staining and immunohistochemistry staining for VEGF.
Results ICGA showed CNV developed,similarly,both in the bevacizumab group and the control group on day 7.But the scores of fluorescein staining at that time were significantly lower in the bevacizumab group.However,the scores soon increased till day 21,but still lower than those of the control group.On day 21,the mean thickness of CNV was significantly reduced in the bevacizumab group.And the CNV in the bevacizumab group were negative for VEGF according to the result of immmuohistochemistry staining.
Conclusions Early intravitreous injection of bevacizumab can inhibit the development of CNV both in morphology and permeability in the BN rat model. However,bevacizumab could neither block the formation of CNV,nor suppress the leakage permanently.Thus,combined therapy with bevacizumab may be more potential to treat CNV effectively.
引文
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[75] Dhalla MS,Shah GK,Blinder KJ,et al.Combined photodynamic therapy with verteporfin and intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration[J].Retina,2006,26:988-993.
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