亚硒酸钠致白内障发病机理的初步研究
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摘要
白内障是一个全球范围内的致盲性眼疾，在所有致盲性眼科疾病中占据的比例最大。白内障目前只有手术治疗，但因其高昂的手术费用及术后并发症是目前的难题。因此，开展白内障的防治研究已成为当前的研究热点。
硒性白内障作为一种实验性动物模型，用以模拟人类的老年性白内障，因其造模迅速、方便，被广泛用于研究白内障形成的各种机制，以及筛选抗白内障药物。有趣的是硒性白内障的产生必须在大鼠开眼之前注射亚硒酸钠，开眼之后即使加大亚硒酸钠的剂量，也无法造模成功，这种年龄上的特异性至今原因不明。而开展这个问题的研究，将有助于进一步揭示硒性白内障的形成机理和硒性白内障模型在抗白内障药物筛选中的应用。
本论文以硒性白内障动物模型和人晶状体上皮（hLE）细胞SRA01/04为实验对象，对血－视网膜屏障的发育与硒性白内障形成的关系、硒诱导晶状体上皮细胞凋亡及其途径等开展了研究。主要结果如下：
1.血－视网膜屏障的发育对大鼠硒性白内障形成的影响
采用文献上的方法，给未开眼的Wistar大鼠幼崽皮下注射亚硒酸钠，成功地造成核性白内障模型。首先，我们检测了不同年龄段Wistar鼠晶状体中谷胱甘肽过氧化物酶（GPx）1、蛋氨酸亚砜还原酶（Msr）A、MsrB1的mRNA表达以及GPx活性，结果表明开眼前幼鼠这些酶mRNA的表达和GPx的酶活性最高，之后随着年龄的增长而逐渐下降。进一步，我们采用氢氧化镧示踪法检测了不同年龄段血－视网膜屏障的发育情况，结果表明，19天龄Wistar鼠视网膜色素上皮层氢氧化镧分布显著少于10天龄幼鼠。对8天龄大鼠注射亚硒酸钠48小时后，氢氧化镧明显增加并延伸到视网膜的内层，视网膜色素上皮层严重损伤；而17天龄Wistar鼠注射相同剂量亚硒酸钠48h后，只有少量的氢氧化镧进入更没有延伸到内层。相对应地，在这些组别鼠的眼球中的硒含量、晶状体中的MDA水平与氢氧化镧分布的变化基本一致。而且在开眼前注射亚硒酸钠的晶状体中，其上皮细胞的损伤程度极明显大于开眼后的大鼠。这些结果表明未开眼Wistar鼠的抗氧化能力不是其易于形成白内障的主要原因，而真正原因是由于未开眼幼鼠血－视网膜屏障发育不成熟，使得大量的亚硒酸钠进入眼中，导致晶状体氧化损伤而出现白内障。
2.硒诱导晶状体上皮细胞的凋亡及其凋亡途径
为了探讨亚硒酸钠诱发幼鼠白内障形成的机理，我们研究了硒诱导hLE细胞SRA01/04凋亡及其途径。采用MTT法测定细胞存活率显示，hLE细胞的存活率随着Na_2SeO_3浓度的增加呈现浓度依赖性下降，在Na_2SeO_3浓度为6μM、8μM时，细胞存活率约在50%左右。用Annexin V-FITC/PI双染色流式分析显示，随着亚硒酸钠浓度的增加，hLE细胞的凋亡率逐渐升高，在6μM时凋亡率为23.8%，8μM时凋亡率已达74.6%。这一结果与Hoechst33258染色定性分析的结果相一致。进一步我们测定了hLE细胞Caspase-3酶活性的变化，结果表明经过7μM亚硒酸钠处理24h后，Caspase-3的酶活性上升了49.4%；相对应地，ROS的水平上升了73.1%，MDA的含量上升了80.5%，而且使得细胞线粒体膜电位有较大程度的降低，线粒体去极化较为明显。由此可见，亚硒酸钠诱发的人晶状体上皮细胞SRA01/04凋亡，与亚硒酸钠诱发产生的活性氧介导的线粒体凋亡途径密切相关。
3.硒性白内障对大鼠肝、肾、脑中氧化－还原平衡的影响
在硒性白内障动物模型中，亚硒酸钠对主要代谢器官氧化还原状态的影响鲜见研究报告，为此我们测定了大鼠硒性白内障模型中肝、肾等组织的抗氧化状态的变化。结果表明，与对照组相比，注射亚硒酸钠使大鼠肝、脑中GPx1的mRNA表达水平下降了25%、20%，但大鼠肾中增加了43.5%；GPx活性的变化趋势也如此。MsrA mRNA表达的变化趋势也类似于GPx1，但注射亚硒酸钠后大鼠肝、肾、脑中MsrB1的mRNA表达水平分别增加了86%、62%、71%。进一步的检测可见，硒性白内障模型动物的肝组织发生明显的氧化应激，与对照组相比，注射亚硒酸钠后大鼠肝中MDA的含量增加了78%，但在肾中减少了29%，而在脑中保持基本不变。这些结果表明，硒性白内障模型大鼠肝和肾的氧化－还原状态已经失去平衡，因此在利用该模型动物进行抗白内障药物的筛选时应考虑这一变化。
Cataract is a kind of worldwide eye diseases leading to blind, occupying the largestproportion in all ophthalmological diseases leading to blind. The current treatment ofcataract is operation merely, but the high cost of operation and post-operationcomplications are currently the most troubled problems. Therefore, to develop theprevention and treatment of cataract has become the current research hotspot.
Selenite cataract, an experimental animal model for simulating human senile cataract,because of its quick and convenient molding, is widely used in investigating variousmechanisms of cataract formation, as well as screening for anti-cataract drugs.Interestingly, selenite cataract appears, only when sodium selenite injection is beforeeyelid opening of the rats; after this time, even increasing the dose of sodium selenite,selenite cataract can not appear. With regard to this age specific phenomenon in themolding process, people do not know the reason, but the beneficial research on this issuewill further reveal the deep reason of selenite cataract formation, and expand theapplication of senelite cataract animal model in screening anti-cataract drugs.
In this dissertation, animal model of selenite cataract and human lens epithelial (hLE)cells SRA01/04were used as the experimental objects, to investigate the relationshipbetween development of blood-retina barrier and selenite cataract formation, also thatbetween selenium and apoptosis pathway of lens epithelial cell, and so on. The mainresults are as followed:
1. Effect of blood-retinal barrier development on formation of selenite nuclearcataract in rat
According to the method in literatures, injection of sodium selenite to eyelidunopening Wistar rats subcutaneously produced nuclear cataract successfully. Initially, wedetected mRNA expression of GPx1, MsrA, MsrB1and activity of GPx in rat lens ofdifferent ages, the results show that mRNA expression of these enzymes and enzymeactivity of GPx were the highest before eyelid opening, and then progressively decreasedwith age. Further, we used lanthanum hydroxide tracer method to detect development status of blood-retina barrier at different ages, the results show that distribution oflanthanum hydroxide in retinal pigment epithelial layer of19-day-old rats wassignificantly less than10-day-old rats. Injecting sodium selenite to8-day-old rats,lanthanum hydroxide increases obviously and extends to the inner layers of the retina after48h, and the retinal pigment epithelial layer was damaged seriously; while injectingsodium selenite to17-day-old rats with the same dose, number of lanthanum hydroxidedecreased significantly and does not extend to the inner layer after48h. Correspondingly,in these groups of rats, selenium content in the eyeballs and MDA level in the lens are inagreement with the change of lanthanum hydroxide distribution. Injecting sodium selenitebefore eyelid unopening, the damage degree of epithelial cells was significantly greaterthan injecting after that. These results indicate that antioxidant capacity in the eyelidunopening rats is not the main reason for easy cataract formation, but the real reason isthat blood-retina barrier development is not mature in the eyelid unopening rats, and thena lot of sodium selenite gets into the eyes, resulting in oxidative damage to eye lens andformation of cataract.
2. Apoptosis of lens epithelial cells induced by selenium and its pathway
In order to study the mechanism of cataract formation induced by sodium selenite,we investigated apoptosis of hLE cells SRA01/04induced by selenium and its pathway.Cell viability was determined by MTT method. The data displayed that, the survival rateof hLE cell showed a concentration-dependent decrease to the increasing concentration ofsodium selenite. When the concentration of Na_2SeO_3is6μM and8μM, the cell survivalrates are about50%. Annexin V-FITC/PI double staining and flow cytometry analysisshowed that, as the increasing concentration of sodium selenite, apoptosis rate of hLE cellincreased gradually: it was23.8%at6μM, however it has reached74.6%at8μM. Thisresult is coincident with the qualitative result of Hoechst33258staining. We furthermeasured the activity change of Caspase-3in hLE cells; the results showed that aftertreatment with7μM sodium selenite for24h, Caspase-3activity increased by49.4%.Correspondingly, level of ROS increased by73.1%, content of MDA increased by80.5%,and the mitochondrial membrane potential is greatly decreased, mitochondrialdepolarization is very obvious. Thus, apoptosis of hLE cells SRA01/04induced by sodium selenite, is closely related to mitochondrial apoptotic pathway mediated by generatedreactive oxygen species.
3. Influence of selenite cataract on redox balance in liver, kidney and brain of Wistarrat
In the animal model of selenite cataract, there is little report on the effect of sodiumselenite on the redox status of major metabolic organ, so we measured the changes ofantioxidant status of some tissues in selenite cataract rat model, such as liver, kidney, etc.The results show that, compared with the control group, injecting sodium selenite to ratsresulting in mRNA expression level of GPx1decreased by25%,20%in liver, brain, butthat in kidney increased by43.5%; the change trend of GPx activity is also like this.Compared to GPx1, mRNA expression of MsrA also presented similar change trend;however, mRNA expression levels of MsrB1increased by86%,62%and71%in rat liver,kidney and brain after injection of sodium selenite. It is shown by further detection,significant oxidative stress appeared in liver tissue of selenite cataract model animal;compared with the control group, after injection of sodium selenite, MDA content in ratliver increased by78%, but reduced by29%in kidney, and remained unchanged in brain.These results indicate that, the balance of redox state in liver and kidney of selenitecataract rat model has been broken, so this change should be taken into account whenscreening anti-cataract drugs by this model animal.
硒性白内障作为一种实验性动物模型，用以模拟人类的老年性白内障，因其造模迅速、方便，被广泛用于研究白内障形成的各种机制，以及筛选抗白内障药物。有趣的是硒性白内障的产生必须在大鼠开眼之前注射亚硒酸钠，开眼之后即使加大亚硒酸钠的剂量，也无法造模成功，这种年龄上的特异性至今原因不明。而开展这个问题的研究，将有助于进一步揭示硒性白内障的形成机理和硒性白内障模型在抗白内障药物筛选中的应用。
本论文以硒性白内障动物模型和人晶状体上皮（hLE）细胞SRA01/04为实验对象，对血－视网膜屏障的发育与硒性白内障形成的关系、硒诱导晶状体上皮细胞凋亡及其途径等开展了研究。主要结果如下：
1.血－视网膜屏障的发育对大鼠硒性白内障形成的影响
采用文献上的方法，给未开眼的Wistar大鼠幼崽皮下注射亚硒酸钠，成功地造成核性白内障模型。首先，我们检测了不同年龄段Wistar鼠晶状体中谷胱甘肽过氧化物酶（GPx）1、蛋氨酸亚砜还原酶（Msr）A、MsrB1的mRNA表达以及GPx活性，结果表明开眼前幼鼠这些酶mRNA的表达和GPx的酶活性最高，之后随着年龄的增长而逐渐下降。进一步，我们采用氢氧化镧示踪法检测了不同年龄段血－视网膜屏障的发育情况，结果表明，19天龄Wistar鼠视网膜色素上皮层氢氧化镧分布显著少于10天龄幼鼠。对8天龄大鼠注射亚硒酸钠48小时后，氢氧化镧明显增加并延伸到视网膜的内层，视网膜色素上皮层严重损伤；而17天龄Wistar鼠注射相同剂量亚硒酸钠48h后，只有少量的氢氧化镧进入更没有延伸到内层。相对应地，在这些组别鼠的眼球中的硒含量、晶状体中的MDA水平与氢氧化镧分布的变化基本一致。而且在开眼前注射亚硒酸钠的晶状体中，其上皮细胞的损伤程度极明显大于开眼后的大鼠。这些结果表明未开眼Wistar鼠的抗氧化能力不是其易于形成白内障的主要原因，而真正原因是由于未开眼幼鼠血－视网膜屏障发育不成熟，使得大量的亚硒酸钠进入眼中，导致晶状体氧化损伤而出现白内障。
2.硒诱导晶状体上皮细胞的凋亡及其凋亡途径
为了探讨亚硒酸钠诱发幼鼠白内障形成的机理，我们研究了硒诱导hLE细胞SRA01/04凋亡及其途径。采用MTT法测定细胞存活率显示，hLE细胞的存活率随着Na_2SeO_3浓度的增加呈现浓度依赖性下降，在Na_2SeO_3浓度为6μM、8μM时，细胞存活率约在50%左右。用Annexin V-FITC/PI双染色流式分析显示，随着亚硒酸钠浓度的增加，hLE细胞的凋亡率逐渐升高，在6μM时凋亡率为23.8%，8μM时凋亡率已达74.6%。这一结果与Hoechst33258染色定性分析的结果相一致。进一步我们测定了hLE细胞Caspase-3酶活性的变化，结果表明经过7μM亚硒酸钠处理24h后，Caspase-3的酶活性上升了49.4%；相对应地，ROS的水平上升了73.1%，MDA的含量上升了80.5%，而且使得细胞线粒体膜电位有较大程度的降低，线粒体去极化较为明显。由此可见，亚硒酸钠诱发的人晶状体上皮细胞SRA01/04凋亡，与亚硒酸钠诱发产生的活性氧介导的线粒体凋亡途径密切相关。
3.硒性白内障对大鼠肝、肾、脑中氧化－还原平衡的影响
在硒性白内障动物模型中，亚硒酸钠对主要代谢器官氧化还原状态的影响鲜见研究报告，为此我们测定了大鼠硒性白内障模型中肝、肾等组织的抗氧化状态的变化。结果表明，与对照组相比，注射亚硒酸钠使大鼠肝、脑中GPx1的mRNA表达水平下降了25%、20%，但大鼠肾中增加了43.5%；GPx活性的变化趋势也如此。MsrA mRNA表达的变化趋势也类似于GPx1，但注射亚硒酸钠后大鼠肝、肾、脑中MsrB1的mRNA表达水平分别增加了86%、62%、71%。进一步的检测可见，硒性白内障模型动物的肝组织发生明显的氧化应激，与对照组相比，注射亚硒酸钠后大鼠肝中MDA的含量增加了78%，但在肾中减少了29%，而在脑中保持基本不变。这些结果表明，硒性白内障模型大鼠肝和肾的氧化－还原状态已经失去平衡，因此在利用该模型动物进行抗白内障药物的筛选时应考虑这一变化。
Cataract is a kind of worldwide eye diseases leading to blind, occupying the largestproportion in all ophthalmological diseases leading to blind. The current treatment ofcataract is operation merely, but the high cost of operation and post-operationcomplications are currently the most troubled problems. Therefore, to develop theprevention and treatment of cataract has become the current research hotspot.
Selenite cataract, an experimental animal model for simulating human senile cataract,because of its quick and convenient molding, is widely used in investigating variousmechanisms of cataract formation, as well as screening for anti-cataract drugs.Interestingly, selenite cataract appears, only when sodium selenite injection is beforeeyelid opening of the rats; after this time, even increasing the dose of sodium selenite,selenite cataract can not appear. With regard to this age specific phenomenon in themolding process, people do not know the reason, but the beneficial research on this issuewill further reveal the deep reason of selenite cataract formation, and expand theapplication of senelite cataract animal model in screening anti-cataract drugs.
In this dissertation, animal model of selenite cataract and human lens epithelial (hLE)cells SRA01/04were used as the experimental objects, to investigate the relationshipbetween development of blood-retina barrier and selenite cataract formation, also thatbetween selenium and apoptosis pathway of lens epithelial cell, and so on. The mainresults are as followed:
1. Effect of blood-retinal barrier development on formation of selenite nuclearcataract in rat
According to the method in literatures, injection of sodium selenite to eyelidunopening Wistar rats subcutaneously produced nuclear cataract successfully. Initially, wedetected mRNA expression of GPx1, MsrA, MsrB1and activity of GPx in rat lens ofdifferent ages, the results show that mRNA expression of these enzymes and enzymeactivity of GPx were the highest before eyelid opening, and then progressively decreasedwith age. Further, we used lanthanum hydroxide tracer method to detect development status of blood-retina barrier at different ages, the results show that distribution oflanthanum hydroxide in retinal pigment epithelial layer of19-day-old rats wassignificantly less than10-day-old rats. Injecting sodium selenite to8-day-old rats,lanthanum hydroxide increases obviously and extends to the inner layers of the retina after48h, and the retinal pigment epithelial layer was damaged seriously; while injectingsodium selenite to17-day-old rats with the same dose, number of lanthanum hydroxidedecreased significantly and does not extend to the inner layer after48h. Correspondingly,in these groups of rats, selenium content in the eyeballs and MDA level in the lens are inagreement with the change of lanthanum hydroxide distribution. Injecting sodium selenitebefore eyelid unopening, the damage degree of epithelial cells was significantly greaterthan injecting after that. These results indicate that antioxidant capacity in the eyelidunopening rats is not the main reason for easy cataract formation, but the real reason isthat blood-retina barrier development is not mature in the eyelid unopening rats, and thena lot of sodium selenite gets into the eyes, resulting in oxidative damage to eye lens andformation of cataract.
2. Apoptosis of lens epithelial cells induced by selenium and its pathway
In order to study the mechanism of cataract formation induced by sodium selenite,we investigated apoptosis of hLE cells SRA01/04induced by selenium and its pathway.Cell viability was determined by MTT method. The data displayed that, the survival rateof hLE cell showed a concentration-dependent decrease to the increasing concentration ofsodium selenite. When the concentration of Na_2SeO_3is6μM and8μM, the cell survivalrates are about50%. Annexin V-FITC/PI double staining and flow cytometry analysisshowed that, as the increasing concentration of sodium selenite, apoptosis rate of hLE cellincreased gradually: it was23.8%at6μM, however it has reached74.6%at8μM. Thisresult is coincident with the qualitative result of Hoechst33258staining. We furthermeasured the activity change of Caspase-3in hLE cells; the results showed that aftertreatment with7μM sodium selenite for24h, Caspase-3activity increased by49.4%.Correspondingly, level of ROS increased by73.1%, content of MDA increased by80.5%,and the mitochondrial membrane potential is greatly decreased, mitochondrialdepolarization is very obvious. Thus, apoptosis of hLE cells SRA01/04induced by sodium selenite, is closely related to mitochondrial apoptotic pathway mediated by generatedreactive oxygen species.
3. Influence of selenite cataract on redox balance in liver, kidney and brain of Wistarrat
In the animal model of selenite cataract, there is little report on the effect of sodiumselenite on the redox status of major metabolic organ, so we measured the changes ofantioxidant status of some tissues in selenite cataract rat model, such as liver, kidney, etc.The results show that, compared with the control group, injecting sodium selenite to ratsresulting in mRNA expression level of GPx1decreased by25%,20%in liver, brain, butthat in kidney increased by43.5%; the change trend of GPx activity is also like this.Compared to GPx1, mRNA expression of MsrA also presented similar change trend;however, mRNA expression levels of MsrB1increased by86%,62%and71%in rat liver,kidney and brain after injection of sodium selenite. It is shown by further detection,significant oxidative stress appeared in liver tissue of selenite cataract model animal;compared with the control group, after injection of sodium selenite, MDA content in ratliver increased by78%, but reduced by29%in kidney, and remained unchanged in brain.These results indicate that, the balance of redox state in liver and kidney of selenitecataract rat model has been broken, so this change should be taken into account whenscreening anti-cataract drugs by this model animal.
引文
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