玻璃体腔注射地塞米松治疗氩激光诱导兔眼视网膜水肿的实验研究
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摘要
目的观察在氩激光诱导的兔眼视网膜水肿模型中，玻璃体腔注射地塞米松（DEX）对视网膜形态学和内皮素-1（ET-1）表达的影响，探讨地塞米松对视网膜水肿的治疗作用及可能机制。
方法健康有色兔40只，随机分为A组（平衡盐溶液对照组）、B组（地塞米松实验组）。A、B组再根据处死时间不同随机分为给药后12h（A1、B1）、1d（A2、B2）、3d（A3、B3）、5d（A4、B4）四个亚组，每亚组5只，均对右眼采用氩激光直接光凝法封闭视网膜主干静脉建立视网膜水肿模型，40只兔左眼不做任何处理设为正常组。A组20只兔在造模后1d右眼玻璃体腔注射平衡盐溶液0.2ml，B组20只兔在造模后1d右眼玻璃体腔注射地塞米松注射液1mg/0.2ml。每只实验兔在造模前、给药前及给药后各预定时间点测量眼压，行OCT检查，然后处死动物，摘取眼球标本，进行HE染色及免疫组化SABC染色，光镜下观察视网膜组织病理学变化及ET-1的表达情况，并应用图像分析对后者进行量化。应用SPSS软件对数据进行析因设计资料的统计学分析。
结果
1．40只有色兔均成功建立视网膜水肿模型。
2．眼压检查：对照组和实验组眼压值总体间差别无统计学意义（P>0.05），不同时间点上眼压值比较差别无统计学意义（P>0.05），并且两组眼压随时间变化趋势基本一致，差别无统计学意义（P>0.05）。
3．OCT检查：在玻璃体腔注药后12h、1d、3d、5d四个观察点上，实验组的视网膜厚度均小于对照组，差别有统计学意义（P<0.05），对照组和实验组的视网膜厚度随时间变化趋势不一致，实验组视网膜厚度逐渐减小，对照组视网膜厚度逐渐增大，差别有统计学意义（P<0.05），且注药后12h分别与注药后3d、5d视网膜厚度相比差别有统计学意义（P<0.05）。
4．光镜观察：正常兔眼视网膜组织排列紧密整齐，层次结构清晰。对照组在注药后12h视网膜层次不规则，神经节细胞肿胀，内外核层有部分细胞水肿；1d时神经节细胞数目减少，呈空泡样变，外丛状层细胞水肿，内外核层排列疏松紊乱、隆起；3d时视网膜各层结构不清，内界膜不连续，表面附着纤维性渗出；5d与3d时比较未见明显变化。实验组在注药后12h视网膜各层结构变化与对照组相似；1d时神经节细胞层偶有空泡样变，内外核层有少量细胞丢失，外丛状层轻度水肿；3d时神经节细胞层未见明显异常，外丛状层有少量细胞轻度肿胀；5d时视网膜各层形态结构大致正常，偶有细胞水肿，明显优于对照组。
5．视网膜ET-1的表达：ET-1在玻璃体腔注药后12h便有表达，并且在注药后12h、1d、3d、5d四个观察点上，实验组ET-1的表达水平明显低于对照组，差别有统计学意义（P<0.05）。对照组和实验组的ET-1表达水平随时间变化趋势不一致，对照组ET-1的表达逐渐增强，在注药后3d、5d有较高表达，实验组ET-1的表达逐渐减弱，下降趋势逐渐减缓，差别有统计学意义（P<0.05）。
结论DEX可以通过抑制ET-1的分泌和释放，短期内迅速有效地减轻视网膜水肿。
Objective：To observe the retinal morphology changes and the effect of endothelin-1 afterintravitreous injection with dexamethasone for retinal edema which was induced by argon laserin rabbit eyes, we explored dexamethasone to the therapy effect of retinal edema and possiblemechanism.
Methods：Forty healthy pigmented rabbits were randomly divided into group A (balance saltsolution control group), group B (DEX intervention group). Group A and group B respectivelyaccording to different killing time were divided into four groups, 12h、1d、3d and 5d after thetreatment, each subgroup had five rabbits. The model of retinal edema was established withargon laser photocoagulation to retinal vein in right eyes of fourty healthy pigmented rabbitsand the forty left eyes of rabbits do nothing as normal control group. The twenty right eyes ofgroup A were intravitreally injected with balance salt solution 0.2ml and the twenty right eyesof group B were intravitreally injected with dexamethasone 1mg / 0.2ml. Intraocular pressure(IOP) and optical coherence tomography (OCT) was performed on each animal before and afterintravitreous injection. After the examination the animal was killed and the eyeballs wereextirpated at the four points of time after the injection. The ultrastructural changes of the retinaand the expressions of ET-1 were observed by light microscopy through HE dyeing andimmunohistochemical staining SABC methods which were quantized by image analysis system.All the datum were analysised by ANOVA of SPSS software.
The results：
1. The models of retina edema were successfully established in forty pigmented rabbits.
2. IOP check: The IOP of the control group and DEX intervention group were generally nosignificant difference (P > 0.05). The IOP of two groups were no significant difference on12 hour, 1 day, 3 day and 5 day after the injection (P > 0.05). The change trend of IOP wasalmost the same over time in two group (P > 0.05).
3. OCT check：The retinal thickness of DEX intervention group was significantly less thanthat saline control group on 12 hour, 1 day, 3 day and 5 day after the intravitreous injection(P < 0.05). The change trend of retinal thickness was inconsistency over time in balance saltcontrol group and DEX intervention group (P < 0.05). The retinal thickness reducedgradually after intravitreous injecting DEX, however, the retinal thickness increasedgradually in saline control group. The retinal thickness after injection 12h respectively with after injection 3d, 5d was statistically significant compared difference (P < 0.05).
4. Histopathologic observation: The normal retina showed clear structure and no degenerationof retinal tissues. The retinal structure in saline control group disordered while retinalganglion cells and parts of inner and outer nuclear layers were swollen on 12 hour aftertreatment; The number of retinal ganglion cells reduce even vanished and externalplexiform layer cells were swollen and the segments of inner and outer nuclear layersbecame collapsed on 1 day; The retinal structure was not clear and fiber proliferated on thesurface of the inner limited membrane on 3 day; The retinal structure of 3 day aftertreatment was equal with 3 day after treatment. The retinal structure of 12 hour in DEXintervention group was similar with 3 day in saline control group; A little of retinal ganglioncells were vacuolated and a little of inner and outer nuclear layers vanished on 1 day;Retinal ganglion cells did not see obvious abnormity and a little of external plexiform layercells were swollen on 3 day; The retinal structure was more clear than saline control groupon 5 day after treatment.
5. ET-1 expression in retinal：The expression of ET-1 had expressed on 12 hour after treatment.The expression of ET-1 in DEX intervention group was significantly less than that salinecontrol group on 12 hour, 1 day, 3 day and 5 day after the intravitreous injection (P < 0.05).The change trend of expression level of ET-1 was inconsistency over time in balance saltcontrol group and DEX intervention group (P < 0.05). The expressions of ET-1 increasedgradually in saline control group, especially on 3 day and 5 day after injection, however, theexpressions of ET-1 reduced gradually after intravitreous injecting DEX and the declinetrend was slowing. Statistically significant compared difference (P < 0.05).ConclusioConclusion：DEX could effectively fast reduce retinal edema through restraining the ET-1from secretion and liberation in short time.
方法健康有色兔40只，随机分为A组（平衡盐溶液对照组）、B组（地塞米松实验组）。A、B组再根据处死时间不同随机分为给药后12h（A1、B1）、1d（A2、B2）、3d（A3、B3）、5d（A4、B4）四个亚组，每亚组5只，均对右眼采用氩激光直接光凝法封闭视网膜主干静脉建立视网膜水肿模型，40只兔左眼不做任何处理设为正常组。A组20只兔在造模后1d右眼玻璃体腔注射平衡盐溶液0.2ml，B组20只兔在造模后1d右眼玻璃体腔注射地塞米松注射液1mg/0.2ml。每只实验兔在造模前、给药前及给药后各预定时间点测量眼压，行OCT检查，然后处死动物，摘取眼球标本，进行HE染色及免疫组化SABC染色，光镜下观察视网膜组织病理学变化及ET-1的表达情况，并应用图像分析对后者进行量化。应用SPSS软件对数据进行析因设计资料的统计学分析。
结果
1．40只有色兔均成功建立视网膜水肿模型。
2．眼压检查：对照组和实验组眼压值总体间差别无统计学意义（P>0.05），不同时间点上眼压值比较差别无统计学意义（P>0.05），并且两组眼压随时间变化趋势基本一致，差别无统计学意义（P>0.05）。
3．OCT检查：在玻璃体腔注药后12h、1d、3d、5d四个观察点上，实验组的视网膜厚度均小于对照组，差别有统计学意义（P<0.05），对照组和实验组的视网膜厚度随时间变化趋势不一致，实验组视网膜厚度逐渐减小，对照组视网膜厚度逐渐增大，差别有统计学意义（P<0.05），且注药后12h分别与注药后3d、5d视网膜厚度相比差别有统计学意义（P<0.05）。
4．光镜观察：正常兔眼视网膜组织排列紧密整齐，层次结构清晰。对照组在注药后12h视网膜层次不规则，神经节细胞肿胀，内外核层有部分细胞水肿；1d时神经节细胞数目减少，呈空泡样变，外丛状层细胞水肿，内外核层排列疏松紊乱、隆起；3d时视网膜各层结构不清，内界膜不连续，表面附着纤维性渗出；5d与3d时比较未见明显变化。实验组在注药后12h视网膜各层结构变化与对照组相似；1d时神经节细胞层偶有空泡样变，内外核层有少量细胞丢失，外丛状层轻度水肿；3d时神经节细胞层未见明显异常，外丛状层有少量细胞轻度肿胀；5d时视网膜各层形态结构大致正常，偶有细胞水肿，明显优于对照组。
5．视网膜ET-1的表达：ET-1在玻璃体腔注药后12h便有表达，并且在注药后12h、1d、3d、5d四个观察点上，实验组ET-1的表达水平明显低于对照组，差别有统计学意义（P<0.05）。对照组和实验组的ET-1表达水平随时间变化趋势不一致，对照组ET-1的表达逐渐增强，在注药后3d、5d有较高表达，实验组ET-1的表达逐渐减弱，下降趋势逐渐减缓，差别有统计学意义（P<0.05）。
结论DEX可以通过抑制ET-1的分泌和释放，短期内迅速有效地减轻视网膜水肿。
Objective：To observe the retinal morphology changes and the effect of endothelin-1 afterintravitreous injection with dexamethasone for retinal edema which was induced by argon laserin rabbit eyes, we explored dexamethasone to the therapy effect of retinal edema and possiblemechanism.
Methods：Forty healthy pigmented rabbits were randomly divided into group A (balance saltsolution control group), group B (DEX intervention group). Group A and group B respectivelyaccording to different killing time were divided into four groups, 12h、1d、3d and 5d after thetreatment, each subgroup had five rabbits. The model of retinal edema was established withargon laser photocoagulation to retinal vein in right eyes of fourty healthy pigmented rabbitsand the forty left eyes of rabbits do nothing as normal control group. The twenty right eyes ofgroup A were intravitreally injected with balance salt solution 0.2ml and the twenty right eyesof group B were intravitreally injected with dexamethasone 1mg / 0.2ml. Intraocular pressure(IOP) and optical coherence tomography (OCT) was performed on each animal before and afterintravitreous injection. After the examination the animal was killed and the eyeballs wereextirpated at the four points of time after the injection. The ultrastructural changes of the retinaand the expressions of ET-1 were observed by light microscopy through HE dyeing andimmunohistochemical staining SABC methods which were quantized by image analysis system.All the datum were analysised by ANOVA of SPSS software.
The results：
1. The models of retina edema were successfully established in forty pigmented rabbits.
2. IOP check: The IOP of the control group and DEX intervention group were generally nosignificant difference (P > 0.05). The IOP of two groups were no significant difference on12 hour, 1 day, 3 day and 5 day after the injection (P > 0.05). The change trend of IOP wasalmost the same over time in two group (P > 0.05).
3. OCT check：The retinal thickness of DEX intervention group was significantly less thanthat saline control group on 12 hour, 1 day, 3 day and 5 day after the intravitreous injection(P < 0.05). The change trend of retinal thickness was inconsistency over time in balance saltcontrol group and DEX intervention group (P < 0.05). The retinal thickness reducedgradually after intravitreous injecting DEX, however, the retinal thickness increasedgradually in saline control group. The retinal thickness after injection 12h respectively with after injection 3d, 5d was statistically significant compared difference (P < 0.05).
4. Histopathologic observation: The normal retina showed clear structure and no degenerationof retinal tissues. The retinal structure in saline control group disordered while retinalganglion cells and parts of inner and outer nuclear layers were swollen on 12 hour aftertreatment; The number of retinal ganglion cells reduce even vanished and externalplexiform layer cells were swollen and the segments of inner and outer nuclear layersbecame collapsed on 1 day; The retinal structure was not clear and fiber proliferated on thesurface of the inner limited membrane on 3 day; The retinal structure of 3 day aftertreatment was equal with 3 day after treatment. The retinal structure of 12 hour in DEXintervention group was similar with 3 day in saline control group; A little of retinal ganglioncells were vacuolated and a little of inner and outer nuclear layers vanished on 1 day;Retinal ganglion cells did not see obvious abnormity and a little of external plexiform layercells were swollen on 3 day; The retinal structure was more clear than saline control groupon 5 day after treatment.
5. ET-1 expression in retinal：The expression of ET-1 had expressed on 12 hour after treatment.The expression of ET-1 in DEX intervention group was significantly less than that salinecontrol group on 12 hour, 1 day, 3 day and 5 day after the intravitreous injection (P < 0.05).The change trend of expression level of ET-1 was inconsistency over time in balance saltcontrol group and DEX intervention group (P < 0.05). The expressions of ET-1 increasedgradually in saline control group, especially on 3 day and 5 day after injection, however, theexpressions of ET-1 reduced gradually after intravitreous injecting DEX and the declinetrend was slowing. Statistically significant compared difference (P < 0.05).ConclusioConclusion：DEX could effectively fast reduce retinal edema through restraining the ET-1from secretion and liberation in short time.
引文
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