兔眼视神经结扎后玻璃体腔内注射尿激酶的视网膜血管穿透能力的实验研究
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摘要
背景和目的
视网膜中央动脉阻塞(central retinal artery occlusion, CRAO)是一种严重的致盲性眼病,是急性视网膜缺血性病变,目前尚无理想的治疗方法。Schmidt等1992首次应用尿激酶选择性眼动脉溶栓技术治疗CRAO获得初步的效果,患者的视网膜水肿减轻、缺血改善、视力显著提高。随着方法不断改进,有研究显示局部介入动脉内溶栓治疗能明显改善视力,但临床有发生偏瘫等严重并发症的报道。这些严重的系统并发症是由于尿激酶的作用范围太广产生的,如果能使尿激酶的作用仅局限在眼内,就能有效的避免中枢神经系统的严重并发症。
尿激酶(Urokinase, UK)是目前临床应用最广泛的溶栓药,用于前房冲洗、结膜下注射等局部治疗未见发生严重并发症的报道。UK属于非纤维蛋白特异性纤溶酶原激活剂,具有半衰期短但降解纤维蛋白原和凝血因子的作用却能持续达12-24小时之久的特点,而且对人体无抗原性,不会引起过敏反应。
Kamei等曾报道玻璃体腔内注射纤溶酶原激活剂能穿透家兔视网膜,并溶解视网膜下血凝块,未见明显副作用。但是玻璃体腔注射纤溶酶原激活剂能否治疗视网膜血管阻塞性疾病,目前尚不清楚。
我们假设存在玻璃体腔注射UK的技术治疗视网膜血管阻塞性疾病的可能性,首先要观察UK能否进入视网膜血管内。本研究通过对兔眼进行视神经结扎后玻璃体腔内注射尿激酶,观察尿激酶的对视网膜血管的穿透能力,从而为玻璃体腔注射UK治疗视网膜血管阻塞性疾病奠定基础。
材料与方法
方法选用健康成年家兔54只,随机分为A、B、C、三组,每组18只,A、B组为实验组,C组为对照组,均以右眼为实验眼。
A组对家兔视神经进行结扎,然后玻璃体腔内注射浓度容量为5000U/0.1ml的尿激酶(Urokinase, UK), B组不做视神经处的结扎处理,直接在玻璃体腔内注射浓度容量为5000U/0.1 ml的尿激酶(Urokinase, UK), C组直接在玻璃体腔内注射0.1ml磷酸缓冲液(Phosphate Buffered Saline, PBS)。
以玻璃体腔内注射后24小时为观察时间点,A、B组分别随机选取10只家兔,C组随机选取2只家兔摘除眼球,制作视网膜组织的石蜡切片,进行视网膜组织常规病理检查和免疫组织化学染色观察尿激酶的渗透能力,使用Nikon DS-Ril生物显微镜进行图像采集并用及Image-Pro Plus 6.0医学专业图像分析软件计算切片中每个血管染色的平均光密度(Mean Optical Density, MOD)值。
统计学处理采用SPSS 17.0软件进行统计学分析,采用两独立样本的检验(t检验)比较,检验水准为a=0.05。
结果
1.渗透进入视网膜血管中UK的定性与定位表达：C组及实验组阴性对照切片的血管腔中均未见阳性表达的棕黄色颗粒,A、B组的免疫组织化学染色的切片中可见阳性表达的棕黄色颗粒, A组阳性表达定位主要在视网膜血管壁、血管腔内和视网膜神经纤维层、神经节细胞层、内丛状层、内核层、外丛状层及外核层。B组均可见沿内界膜表面呈棕黄色的带状分布,在视网膜血管壁及其他层次内也可以见棕黄色颗粒。
2.UK的视网膜血管穿透能力分析：A组免疫组织化学染色切片中可见视网膜血管腔和其他各层内有棕黄色颗粒, B组免疫组织化学染色切片均可见沿内界膜表面呈棕黄色的带状分布,在视网膜血管壁及其他层次内也可以见棕黄色颗粒,但是视网膜血管腔内未见棕黄色颗粒。
玻璃体腔内注射相同药物浓度和作用时间A组与B组间视网膜血管穿透能力的比较：视神经结扎和无视神经结扎因素,两组间UK的视网膜血管穿透能力的差别具有统计学意义(t=14.603,p<0.05)。
3.尿激酶的视网膜毒性作用：C组家兔视网膜结构完整,各层次结构完整,排列整齐规则。B组视网膜表面光滑,视网膜各层分界清晰,外核层细胞数量有减少,内外核层细胞核间隙稍稀疏,其余层次未见明显变化。可见5000U/0.1ml的尿激酶对视网膜组织有一定的毒性作用。
结论
1.兔眼视神经结扎后1小时玻璃体腔内注射的尿激酶,24小时后能够穿透视网膜血管壁进入视网膜血管腔内。
2.尿激酶对视网膜组织有一定的毒性作用。
Background and Objective
Central retinal artery occlusion(CRAO) is a serious disease which can lead the eyes to grow blind,it is retinal acute ischemia but we have not a ideal methods to treat it.Schmidt first applied urokinase for Selectivity ophthalmic artery thrombolysis in clinic in 1992,and it can relieve patients'retinal edema and improve retinal ischemia and eyesight.With the thrombolysis methods improve,some studys imply that local intervention thrombolysis can improve eyesight.but there are strict standards about case's internalize and reject to decide whether use local intervention thrombolysis to treat it,meanwhile it brings troubles to patient's treatment,evenmore there are some serious complications case reports such as hemiplegia. Those complications are resulted in Urokinase's widely effect, if we can find a method which can limit Urokinase's effect in eye, we can clearly avoid those central nerve system's serious complications.
Urokinase(UK) is a most widely clinical application thrombolytic drug at present, there is not serious complication case reports when UK is used to anterior chamber flush、subconjunctival injection.UK is non-fibrin specificity plasminogen activator which have short half life and long time effectiveness as 12-24 hours for degrdn fibrin and blood coagulation factor,moreover it is no antigenicity for human body,it can not lead to anaphylactic response.
Kamei find that intravitreal inject plasminogen activator can through retina into the subretinal space and lyse the subretinal clot in rabbits, and not find obvious side effects.But whether intravitreal inject plasminogen activator can treat the retinal vascular occlusion is not yet clear.
We assumpt that there ia a possibility intravitreal inject UK can treat the retinal vascular occlusion, then we first need to observe if UK can penetrate the retinal vessel.This study injected urokinase into the uitreous cavity after ligate the optic nerve in rabbits to determine if urokinase injected into the vitreous cavity can penetrate the retinal vessels of rabbit eyes so that we can establish foundation of intravitreal inject UK treat the retinal vascular occlusion.
Materials and Methods
54 young rabbits were randomly divided into A, B and C 3 groups (18 in each group, respectively), A, B, and C. A、B groups as the experimental groups, C as the control group. Right eye of all animals were used as the study.
Group A underwent temporary ligation of the optic nerve, and one eye of each rabbit was injected with the experimental groups were given 5000U/0.1ml of UK, one eye of each rabbit of group B was injected 5000U/0.1ml of UK without ligation of the optic nerve. An equivalent volume of 0.01ml sterile phosphate buffered saline (PBS) was injected into group C as control.
Ten samples of right eyes in group A,B and two samples in group C were taken for pathological examinations and immunohistochemistry (IHC) study with the paraffin-embedded sections by scarifying the rabbits at 24 hours after intravitreal injection for each group.Image acquisition data can be obtained from Nikon DS-Ril biomicroscopy and compute the data of mean optical density (MOD) of each section with Image-Pro Plus 6.0 image analysis software.
Statistical Treatment
These datas of each section's Density Mean were analyzed by statistical software SPSS 17.0. Independent-Sample T Test was used to analyze the difference between the different groups.α=0.05 was considered as the level of tests.
Results
(1)The histomorphology of rabbit retina was observed with HE stained paraffin-embedded sections. the structure and morphology of retina in C group was prepared as standard control, no clearly histomorphology changing in group C was observed. However, cells reducing and wide nucleus gaps in INL and ONL was observed for both A and B groups and clear boundaries between retinal layer and smooth surface only in group B be found. edema of retinal surface and vague boundaries as well as appearing of irregular array of the structure of retina and vascular endothelial cell loose arrange in A group were revealed. Besides, some cells with wider nucleus gaps in INL and ONL can also be detected.
(2) Immunohistochemistry analysis of the sample tissues has shown all negative in control (group C). Meanwhile, the control sections of experimental groups were also negative being compared to all other experimental groups that show positive expressions.Positive expression at inner limiting membrane(ILM),retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL),inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL)and cavity of the Retinal vessel could be found in group A. group B revealed positive expression at retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL), and inner nuclear layer (INL).
The structure and morphology of retina in C group was prepared as standard control, In comparison of the penetration for two groups A and B by Independent-Sample T Test at the same doses and the same time point, with or without ligation of the optic nerve, The differences between two groups had statistical significance (t=14.603, p<0.05).
(3)Retinal toxicity of urokinase:no clearly histomorphology changing in group C was observed; meanwhile cells reducing,wide nucleus gaps in ONL, clear boundaries between retinal layer and smooth surface be found in group B.So we can know that the dose of 5000U/0.1ml UK have retinal toxicity.
Conclusions
(1) Urokinase injected into the vitreous cavity for 24 hours can penetrate the retinal vessel after ligation of the optic nerve in rabbits.
(2) Urokinase has retinal toxicity.
视网膜中央动脉阻塞(central retinal artery occlusion, CRAO)是一种严重的致盲性眼病,是急性视网膜缺血性病变,目前尚无理想的治疗方法。Schmidt等1992首次应用尿激酶选择性眼动脉溶栓技术治疗CRAO获得初步的效果,患者的视网膜水肿减轻、缺血改善、视力显著提高。随着方法不断改进,有研究显示局部介入动脉内溶栓治疗能明显改善视力,但临床有发生偏瘫等严重并发症的报道。这些严重的系统并发症是由于尿激酶的作用范围太广产生的,如果能使尿激酶的作用仅局限在眼内,就能有效的避免中枢神经系统的严重并发症。
尿激酶(Urokinase, UK)是目前临床应用最广泛的溶栓药,用于前房冲洗、结膜下注射等局部治疗未见发生严重并发症的报道。UK属于非纤维蛋白特异性纤溶酶原激活剂,具有半衰期短但降解纤维蛋白原和凝血因子的作用却能持续达12-24小时之久的特点,而且对人体无抗原性,不会引起过敏反应。
Kamei等曾报道玻璃体腔内注射纤溶酶原激活剂能穿透家兔视网膜,并溶解视网膜下血凝块,未见明显副作用。但是玻璃体腔注射纤溶酶原激活剂能否治疗视网膜血管阻塞性疾病,目前尚不清楚。
我们假设存在玻璃体腔注射UK的技术治疗视网膜血管阻塞性疾病的可能性,首先要观察UK能否进入视网膜血管内。本研究通过对兔眼进行视神经结扎后玻璃体腔内注射尿激酶,观察尿激酶的对视网膜血管的穿透能力,从而为玻璃体腔注射UK治疗视网膜血管阻塞性疾病奠定基础。
材料与方法
方法选用健康成年家兔54只,随机分为A、B、C、三组,每组18只,A、B组为实验组,C组为对照组,均以右眼为实验眼。
A组对家兔视神经进行结扎,然后玻璃体腔内注射浓度容量为5000U/0.1ml的尿激酶(Urokinase, UK), B组不做视神经处的结扎处理,直接在玻璃体腔内注射浓度容量为5000U/0.1 ml的尿激酶(Urokinase, UK), C组直接在玻璃体腔内注射0.1ml磷酸缓冲液(Phosphate Buffered Saline, PBS)。
以玻璃体腔内注射后24小时为观察时间点,A、B组分别随机选取10只家兔,C组随机选取2只家兔摘除眼球,制作视网膜组织的石蜡切片,进行视网膜组织常规病理检查和免疫组织化学染色观察尿激酶的渗透能力,使用Nikon DS-Ril生物显微镜进行图像采集并用及Image-Pro Plus 6.0医学专业图像分析软件计算切片中每个血管染色的平均光密度(Mean Optical Density, MOD)值。
统计学处理采用SPSS 17.0软件进行统计学分析,采用两独立样本的检验(t检验)比较,检验水准为a=0.05。
结果
1.渗透进入视网膜血管中UK的定性与定位表达：C组及实验组阴性对照切片的血管腔中均未见阳性表达的棕黄色颗粒,A、B组的免疫组织化学染色的切片中可见阳性表达的棕黄色颗粒, A组阳性表达定位主要在视网膜血管壁、血管腔内和视网膜神经纤维层、神经节细胞层、内丛状层、内核层、外丛状层及外核层。B组均可见沿内界膜表面呈棕黄色的带状分布,在视网膜血管壁及其他层次内也可以见棕黄色颗粒。
2.UK的视网膜血管穿透能力分析：A组免疫组织化学染色切片中可见视网膜血管腔和其他各层内有棕黄色颗粒, B组免疫组织化学染色切片均可见沿内界膜表面呈棕黄色的带状分布,在视网膜血管壁及其他层次内也可以见棕黄色颗粒,但是视网膜血管腔内未见棕黄色颗粒。
玻璃体腔内注射相同药物浓度和作用时间A组与B组间视网膜血管穿透能力的比较：视神经结扎和无视神经结扎因素,两组间UK的视网膜血管穿透能力的差别具有统计学意义(t=14.603,p<0.05)。
3.尿激酶的视网膜毒性作用：C组家兔视网膜结构完整,各层次结构完整,排列整齐规则。B组视网膜表面光滑,视网膜各层分界清晰,外核层细胞数量有减少,内外核层细胞核间隙稍稀疏,其余层次未见明显变化。可见5000U/0.1ml的尿激酶对视网膜组织有一定的毒性作用。
结论
1.兔眼视神经结扎后1小时玻璃体腔内注射的尿激酶,24小时后能够穿透视网膜血管壁进入视网膜血管腔内。
2.尿激酶对视网膜组织有一定的毒性作用。
Background and Objective
Central retinal artery occlusion(CRAO) is a serious disease which can lead the eyes to grow blind,it is retinal acute ischemia but we have not a ideal methods to treat it.Schmidt first applied urokinase for Selectivity ophthalmic artery thrombolysis in clinic in 1992,and it can relieve patients'retinal edema and improve retinal ischemia and eyesight.With the thrombolysis methods improve,some studys imply that local intervention thrombolysis can improve eyesight.but there are strict standards about case's internalize and reject to decide whether use local intervention thrombolysis to treat it,meanwhile it brings troubles to patient's treatment,evenmore there are some serious complications case reports such as hemiplegia. Those complications are resulted in Urokinase's widely effect, if we can find a method which can limit Urokinase's effect in eye, we can clearly avoid those central nerve system's serious complications.
Urokinase(UK) is a most widely clinical application thrombolytic drug at present, there is not serious complication case reports when UK is used to anterior chamber flush、subconjunctival injection.UK is non-fibrin specificity plasminogen activator which have short half life and long time effectiveness as 12-24 hours for degrdn fibrin and blood coagulation factor,moreover it is no antigenicity for human body,it can not lead to anaphylactic response.
Kamei find that intravitreal inject plasminogen activator can through retina into the subretinal space and lyse the subretinal clot in rabbits, and not find obvious side effects.But whether intravitreal inject plasminogen activator can treat the retinal vascular occlusion is not yet clear.
We assumpt that there ia a possibility intravitreal inject UK can treat the retinal vascular occlusion, then we first need to observe if UK can penetrate the retinal vessel.This study injected urokinase into the uitreous cavity after ligate the optic nerve in rabbits to determine if urokinase injected into the vitreous cavity can penetrate the retinal vessels of rabbit eyes so that we can establish foundation of intravitreal inject UK treat the retinal vascular occlusion.
Materials and Methods
54 young rabbits were randomly divided into A, B and C 3 groups (18 in each group, respectively), A, B, and C. A、B groups as the experimental groups, C as the control group. Right eye of all animals were used as the study.
Group A underwent temporary ligation of the optic nerve, and one eye of each rabbit was injected with the experimental groups were given 5000U/0.1ml of UK, one eye of each rabbit of group B was injected 5000U/0.1ml of UK without ligation of the optic nerve. An equivalent volume of 0.01ml sterile phosphate buffered saline (PBS) was injected into group C as control.
Ten samples of right eyes in group A,B and two samples in group C were taken for pathological examinations and immunohistochemistry (IHC) study with the paraffin-embedded sections by scarifying the rabbits at 24 hours after intravitreal injection for each group.Image acquisition data can be obtained from Nikon DS-Ril biomicroscopy and compute the data of mean optical density (MOD) of each section with Image-Pro Plus 6.0 image analysis software.
Statistical Treatment
These datas of each section's Density Mean were analyzed by statistical software SPSS 17.0. Independent-Sample T Test was used to analyze the difference between the different groups.α=0.05 was considered as the level of tests.
Results
(1)The histomorphology of rabbit retina was observed with HE stained paraffin-embedded sections. the structure and morphology of retina in C group was prepared as standard control, no clearly histomorphology changing in group C was observed. However, cells reducing and wide nucleus gaps in INL and ONL was observed for both A and B groups and clear boundaries between retinal layer and smooth surface only in group B be found. edema of retinal surface and vague boundaries as well as appearing of irregular array of the structure of retina and vascular endothelial cell loose arrange in A group were revealed. Besides, some cells with wider nucleus gaps in INL and ONL can also be detected.
(2) Immunohistochemistry analysis of the sample tissues has shown all negative in control (group C). Meanwhile, the control sections of experimental groups were also negative being compared to all other experimental groups that show positive expressions.Positive expression at inner limiting membrane(ILM),retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL),inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL)and cavity of the Retinal vessel could be found in group A. group B revealed positive expression at retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL), and inner nuclear layer (INL).
The structure and morphology of retina in C group was prepared as standard control, In comparison of the penetration for two groups A and B by Independent-Sample T Test at the same doses and the same time point, with or without ligation of the optic nerve, The differences between two groups had statistical significance (t=14.603, p<0.05).
(3)Retinal toxicity of urokinase:no clearly histomorphology changing in group C was observed; meanwhile cells reducing,wide nucleus gaps in ONL, clear boundaries between retinal layer and smooth surface be found in group B.So we can know that the dose of 5000U/0.1ml UK have retinal toxicity.
Conclusions
(1) Urokinase injected into the vitreous cavity for 24 hours can penetrate the retinal vessel after ligation of the optic nerve in rabbits.
(2) Urokinase has retinal toxicity.
引文
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