益气活血法对糖尿病大鼠视网膜微血管病变的影响
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摘要
目的：糖尿病性视网膜病变(Diabetil retmapathy, DR)是糖尿病(diabetic mellitus, DM)最为常见和严重的微血管并发症之一,早期预防DR的发生发展一直是国内外学者研究的热点。DR的早期病理改变主要是内皮细胞增生,周细胞选择性丢失和基底膜的增厚,导致毛细血管的高通透性。这些改变与早期糖基化终产物的沉积,细胞间黏附分子表达增加促进白细胞的异常黏附,血管内皮生长因子(VEGF)和色素上皮衍生因子(PEDF)表达失衡等有关。从中医角度看糖尿病发展至DR阶段,是一个本虚标实,虚实夹杂的证候,本虚以阴虚、气虚、阳虚为主,淤血、痰凝为标,其中淤血是贯穿于始终的。如何利用中医药预防早期DR发生和延缓其发展一直是我们关注的焦点。我们在前期的工作中用益气法使用大补元气的中药红参对DR的作用中发现,益气法从病理形态学表现可以减轻视网膜微血管的损伤,还可以明显改善糖尿病大鼠的体重,提示益气药物不但能延缓糖尿病大鼠视网膜病变的进展,还可改善糖尿病大鼠的生存状态。也有学者做过活血通络法对DR的影响,也证实有效。面对DR局部“血瘀”和全身“体虚”的状态,我们确立了益气活血的治则,从组织形态学和分子生物学水平研究其对糖尿病视网膜微血管病变的早期干预作用,并探讨其作用机理,为临床合理选用中药防治DR提供客观的实验基础。
方法：本实验用链脲佐菌素(65mg/kg)一次性腹腔注射的方法建立糖尿病大鼠模型,分为正常组12只,模型组20只,对照组20只与芪参益气滴丸组(简称中药组)30只。中药组芪参益气滴丸浸膏每日(0.2g/kg.d-1)灌胃给药,对照组予多贝斯胶囊每日(0.2g/kg.d-1)灌胃给药。300天后处死动物取血后测血清血管内皮生长因子(VEGF)和细胞间粘附分子-1(ICAM-1).并进行视网膜血管消化铺片形态学观察；视网膜消化铺片基础上免疫组织化学染色观察VEGF和ICAM-1的表达,视网膜切片基础上免疫组化观察VEGF,色素上皮衍生因子(PEDF),糖基化终产物(AGEs)的表达；利用逆转录-聚合酶链式反应(RT-PCR)观察视网膜VEGF, PEDF, ICAM-1和糖基化终产物受体(RAGE)的基因表达。用图象分析仪测量免疫组化显色强度,进行定量分析。采用SPSS 13.0统计软件对数据进行分析处理。
结果：(1)实验期间模型组、中药组、对照组的血糖始终高于正常组(P<0.01)。模型组、中药组、对照组的血糖组间差异不显著。(2)实验期间模型组、中药组、对照组的体重始终低于正常组(P<0.01)。模型组、中药组、对照组的体重组间差异不显著。(3)模型组、中药组、对照组的血清VEGF和ICAM-1含量比正常组升高,但组间无显著性差异。(4)10个月糖尿病大鼠出现了内皮细胞增生,周细胞减少,无细胞毛细血管、影周细胞等DR的特征性改变。早期用药干预后,视网膜病变明显改善。模型组同正常组比内皮细胞增生明显,周细胞明显减少(P<0.01)。而中药组、对照组同模型组比这种改变明显减轻(P<0.01),E/P有显著性差异。(5)模型组的视网膜毛细血管VEGF和ICAM-1表达比正常组明显增强(P<0.01)。中药组和对照组表达比模型组表达降低(P<0.01)。(6)模型组的视网膜VEGF和AGEs的表达比正常组明显增强(P<0.01),中药组和对照组表达比模型组降低(P<0.01)。模型组的视网膜PEDF表达比对照组明显降低(P<0.01),中药组和对照组表达比模型组增加(P<0.01)。(7)模型组的视网膜VEGFmRNA、ICAM-1 mRNA和RAGEmRNA的表达比正常组明显增强(P<0.01),中药组和对照组表达比模型组降低(P<0.01)。模型组视网膜PEDFmRNA的表达比正常组明显降低(P<0.01),中药组和对照组的表达比模型组明显增加(P<0.01)。
结论：(1)益气活血法早期干预从病理形态学观察可减轻糖尿病大鼠早期视网膜病变微血管的损伤。(2)益气活血法可能降低糖尿病大鼠视网膜AGEs和RAGE mRNA的表达,减轻AGEs在内皮细胞、周细胞及基底膜沉积,减少对内皮细胞的刺激,减少VEGF的产生从而减轻毛细血管壁的功能障碍；(3)益气活血法可能通过降低视网膜毛细血管ICAM-1和视网膜ICAM-1 mRNA的表达,减轻白细胞与血管内皮细胞粘附；
(4)益气活血法可能通过降低视网膜全层和毛细血管VEGF和视网膜VEGF mRNA的表达,减轻血管的通透性,可能下调ICAM-1的表达；(5)益气活血法可能通过增加视网膜PEDF和PEDF mRNA的表达,以抑制血管形成。
Purpose:Diabetic retinopathy (DR) is one of the most common and serious microvascular complication of diabetes mellitus (DM),and the main reason leading to blindness as well. The cause of the disease has yet to be determined. In addition, there are no definite and effective measures to prevent it in the early stage.To study the cause of the disease and to find effective drug are the hot spot in each country's ophthalmology. The research of the mechanism involves in biochemistry、molecular biology and blood dyscrasia,but it's center still is high blood sugar which causes a series changes of ischemia and hypoxia. Thanks to its peculiar theory and treatment, traditional Chinese medicine has achieved some success in the prevention and treatment of DR. According to the principle of curing illness from the origin.We select the traditional Chinese medicine QiShenYiQi Gutta Pills(QGP) to YiQiHuoXue Therefore,an attempt is made in this paper to construct a rat model of DM to made a further research into the mechanism of QiShenYiQi Gutta Pills in the prevension of DR in its early stage.
Methods:The diabetic rat model was established by one-time injection of streptozotozin (STZ,65mg/kg). All SD rats (n=82) were randomly divided into the normal group,model group,control group and QGP group. The extractum of QGP (0.2g/(kg.d)) was administrated intragastrically and the same as the extractum of DuoBeiSi (0.2g/(kg.d)).After 10 months, the rats were killed and the eyeballs were collected for the observation of retina. The expression of VEGF and ICAM-1 in retinal microvascular were detected by using immunohistochemistry method,the expression of VEGF、AGEs and PEDF in retina were detected by using immunohistochemistry method, and ICAM-1 mRNA、VEGF mRNA、RAGE mRNA and PEDF mRNA were examined by using reverse transcription-polymerase chain reaction(RT-PCR).The blood samples were collected from rats for detecting the serum content of VEGF and ICAM-1. Immunological histochemistry assay was used for quantitative analysis. SPSS was used for statistical analysis.
Reaults:(1)The content of glucose were higher in the model group,control group and QGP group than that in the normal group, (p<0.01), and were lower in the control group and QGP group than that in the model group,but had no statistical significantly. (2) The weight were lower in the model group,control group and QGP group than that in the normal group, (p<0.01), and were higher in the control group and QGP group than that in the model group,but had no statistical significantly. (3) The serum content of VEGF and ICAM-1 were higher in the model group,control group and QGP group than that in the normal group,and were lower in the control group and QGP group than that in the model group,but had no statistical significantly. (4)Ten months later, DM rats displayed some early symptoms of DR, such as extensive pericyte loss, endothelial cell proliferation, pericyte ghost, and acelluar capillary. After treatment of QGP, the retinopathy has improved remarkably. (5) The expressions of retinal capillary VEGF and ICAM-1 were higher significantly in the model group than those in the normal group,and were lower significantly in the control group and QGP group than that in the model group with a significant difference(p<0.01). (6) The expressions of retinal VEGF and AGEs were higher significantly in the model group than those in the normal group,and were lower significantly in the control group and QGP group than those in the model group with a significant difference(p<0.01). The expression of retinal PEDF was lower significantly in the model group than that in the normal group,and was higher significantly in the control group and QGP group than that in the model group with a significant difference(p<0.01). (7) The expressions of retinal VEGFmRNA、ICAM-1 mRNA and RAGEmRNAwere higher significantly in the model group than those in the normal group,and were lower significantly in the control group and QGP group than those in the model group with a significant difference(p<0.01). The expression of retinal PEDFmRNA was lower significantly in the model group than that in the normal group,and was higher significantly in the control group and QGP group than that in the model group with a significant difference(p<0.01).
Conclusion:YiQiHuoXue method (QiShenYiQi Gutta Pills)can delay the occurrence and development of diabetic retinopathy in rats through decreasing the expressions of retinal VEGF VEGFmRNA、ICAM-1、ICAM-1 mRNA、AGEs and RAGEmRNA, and increasing the expressions of retinal PEDF and PEDFmRNA.
方法：本实验用链脲佐菌素(65mg/kg)一次性腹腔注射的方法建立糖尿病大鼠模型,分为正常组12只,模型组20只,对照组20只与芪参益气滴丸组(简称中药组)30只。中药组芪参益气滴丸浸膏每日(0.2g/kg.d-1)灌胃给药,对照组予多贝斯胶囊每日(0.2g/kg.d-1)灌胃给药。300天后处死动物取血后测血清血管内皮生长因子(VEGF)和细胞间粘附分子-1(ICAM-1).并进行视网膜血管消化铺片形态学观察；视网膜消化铺片基础上免疫组织化学染色观察VEGF和ICAM-1的表达,视网膜切片基础上免疫组化观察VEGF,色素上皮衍生因子(PEDF),糖基化终产物(AGEs)的表达；利用逆转录-聚合酶链式反应(RT-PCR)观察视网膜VEGF, PEDF, ICAM-1和糖基化终产物受体(RAGE)的基因表达。用图象分析仪测量免疫组化显色强度,进行定量分析。采用SPSS 13.0统计软件对数据进行分析处理。
结果：(1)实验期间模型组、中药组、对照组的血糖始终高于正常组(P<0.01)。模型组、中药组、对照组的血糖组间差异不显著。(2)实验期间模型组、中药组、对照组的体重始终低于正常组(P<0.01)。模型组、中药组、对照组的体重组间差异不显著。(3)模型组、中药组、对照组的血清VEGF和ICAM-1含量比正常组升高,但组间无显著性差异。(4)10个月糖尿病大鼠出现了内皮细胞增生,周细胞减少,无细胞毛细血管、影周细胞等DR的特征性改变。早期用药干预后,视网膜病变明显改善。模型组同正常组比内皮细胞增生明显,周细胞明显减少(P<0.01)。而中药组、对照组同模型组比这种改变明显减轻(P<0.01),E/P有显著性差异。(5)模型组的视网膜毛细血管VEGF和ICAM-1表达比正常组明显增强(P<0.01)。中药组和对照组表达比模型组表达降低(P<0.01)。(6)模型组的视网膜VEGF和AGEs的表达比正常组明显增强(P<0.01),中药组和对照组表达比模型组降低(P<0.01)。模型组的视网膜PEDF表达比对照组明显降低(P<0.01),中药组和对照组表达比模型组增加(P<0.01)。(7)模型组的视网膜VEGFmRNA、ICAM-1 mRNA和RAGEmRNA的表达比正常组明显增强(P<0.01),中药组和对照组表达比模型组降低(P<0.01)。模型组视网膜PEDFmRNA的表达比正常组明显降低(P<0.01),中药组和对照组的表达比模型组明显增加(P<0.01)。
结论：(1)益气活血法早期干预从病理形态学观察可减轻糖尿病大鼠早期视网膜病变微血管的损伤。(2)益气活血法可能降低糖尿病大鼠视网膜AGEs和RAGE mRNA的表达,减轻AGEs在内皮细胞、周细胞及基底膜沉积,减少对内皮细胞的刺激,减少VEGF的产生从而减轻毛细血管壁的功能障碍；(3)益气活血法可能通过降低视网膜毛细血管ICAM-1和视网膜ICAM-1 mRNA的表达,减轻白细胞与血管内皮细胞粘附；
(4)益气活血法可能通过降低视网膜全层和毛细血管VEGF和视网膜VEGF mRNA的表达,减轻血管的通透性,可能下调ICAM-1的表达；(5)益气活血法可能通过增加视网膜PEDF和PEDF mRNA的表达,以抑制血管形成。
Purpose:Diabetic retinopathy (DR) is one of the most common and serious microvascular complication of diabetes mellitus (DM),and the main reason leading to blindness as well. The cause of the disease has yet to be determined. In addition, there are no definite and effective measures to prevent it in the early stage.To study the cause of the disease and to find effective drug are the hot spot in each country's ophthalmology. The research of the mechanism involves in biochemistry、molecular biology and blood dyscrasia,but it's center still is high blood sugar which causes a series changes of ischemia and hypoxia. Thanks to its peculiar theory and treatment, traditional Chinese medicine has achieved some success in the prevention and treatment of DR. According to the principle of curing illness from the origin.We select the traditional Chinese medicine QiShenYiQi Gutta Pills(QGP) to YiQiHuoXue Therefore,an attempt is made in this paper to construct a rat model of DM to made a further research into the mechanism of QiShenYiQi Gutta Pills in the prevension of DR in its early stage.
Methods:The diabetic rat model was established by one-time injection of streptozotozin (STZ,65mg/kg). All SD rats (n=82) were randomly divided into the normal group,model group,control group and QGP group. The extractum of QGP (0.2g/(kg.d)) was administrated intragastrically and the same as the extractum of DuoBeiSi (0.2g/(kg.d)).After 10 months, the rats were killed and the eyeballs were collected for the observation of retina. The expression of VEGF and ICAM-1 in retinal microvascular were detected by using immunohistochemistry method,the expression of VEGF、AGEs and PEDF in retina were detected by using immunohistochemistry method, and ICAM-1 mRNA、VEGF mRNA、RAGE mRNA and PEDF mRNA were examined by using reverse transcription-polymerase chain reaction(RT-PCR).The blood samples were collected from rats for detecting the serum content of VEGF and ICAM-1. Immunological histochemistry assay was used for quantitative analysis. SPSS was used for statistical analysis.
Reaults:(1)The content of glucose were higher in the model group,control group and QGP group than that in the normal group, (p<0.01), and were lower in the control group and QGP group than that in the model group,but had no statistical significantly. (2) The weight were lower in the model group,control group and QGP group than that in the normal group, (p<0.01), and were higher in the control group and QGP group than that in the model group,but had no statistical significantly. (3) The serum content of VEGF and ICAM-1 were higher in the model group,control group and QGP group than that in the normal group,and were lower in the control group and QGP group than that in the model group,but had no statistical significantly. (4)Ten months later, DM rats displayed some early symptoms of DR, such as extensive pericyte loss, endothelial cell proliferation, pericyte ghost, and acelluar capillary. After treatment of QGP, the retinopathy has improved remarkably. (5) The expressions of retinal capillary VEGF and ICAM-1 were higher significantly in the model group than those in the normal group,and were lower significantly in the control group and QGP group than that in the model group with a significant difference(p<0.01). (6) The expressions of retinal VEGF and AGEs were higher significantly in the model group than those in the normal group,and were lower significantly in the control group and QGP group than those in the model group with a significant difference(p<0.01). The expression of retinal PEDF was lower significantly in the model group than that in the normal group,and was higher significantly in the control group and QGP group than that in the model group with a significant difference(p<0.01). (7) The expressions of retinal VEGFmRNA、ICAM-1 mRNA and RAGEmRNAwere higher significantly in the model group than those in the normal group,and were lower significantly in the control group and QGP group than those in the model group with a significant difference(p<0.01). The expression of retinal PEDFmRNA was lower significantly in the model group than that in the normal group,and was higher significantly in the control group and QGP group than that in the model group with a significant difference(p<0.01).
Conclusion:YiQiHuoXue method (QiShenYiQi Gutta Pills)can delay the occurrence and development of diabetic retinopathy in rats through decreasing the expressions of retinal VEGF VEGFmRNA、ICAM-1、ICAM-1 mRNA、AGEs and RAGEmRNA, and increasing the expressions of retinal PEDF and PEDFmRNA.
引文
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