温肾方对亚临床甲减大鼠血管损伤的影响的实验研究
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摘要
目的：观察温肾方对亚临床甲减大鼠血管损伤的影响并探讨造成这种影响的机理；
方法：将健康6周龄SPF级Wistar大鼠50只随机抽取8只设为正常对照组。而将正常对照组以外的大鼠行“甲状腺全切+术后皮下注射L-T4”法制备亚临床甲减大鼠模型,造模成功后将这些大鼠随机分为模型组,中药小剂量组,西药组,中药大剂量组。然后对此四组的大鼠行连续30天的灌胃治疗,然后
1.采用化学发光法检测大鼠血清甲功三项的含量,采用Elisa法检测肝脏组织TT3的含量；
2.运用东芝DBA-120型全自动生化分析仪对所有实验大鼠的血脂四项(TC、TG、LDL-C、HDL-C)的浓度进行检测；
3.对大鼠的肝组织中HMG-CoA还原酶及血清中MCP-1, ET-1的水平采用Elisa法进行检测；
4.取出大鼠胸主动脉2cm,匀浆,取其上清液,提取总RNA,利用RT-PCR技术进行基因片段的体外扩增,扩增产物通过电泳后,通过对其电泳照片上灰度值进行检测,比较其LOX-1mRNA的相对含量；
5.于灌胃结束后的第二天在实验大鼠身上取材,取出大鼠胸主动脉标本,制备病理标本,通过光镜和电镜观察实验大鼠胸主动脉显微结构与超微结构；
结果：1.与正常组比较,模型组大鼠血清TSH水平明显升高(P<0.01)。与模型组比较,中药小剂量组TSH水平较明显降低(P<0.05)；西药组TSH水平明显降低(P<0.05)；中药大剂量组TSH水平明显降低(P<0.05)。各组之间FT3, FT4水平无明显差异(P<0.05)模型组肝脏TT3含量,与正常组比较,有明显降低(P<0.05)；中药大剂量组,中药小剂量组,西药组肝脏TT3含量均较模型组明显提高(P<0.05),而其中尤以中药大剂量组的提高最为明显；
2.中药大剂量组,与对照组比较,血浆TC, TG, LDL-C, HDL-C水平没有明显差异(P>0.05)；,与中药小剂量组比较,血脂四项的水平没有明显差异(P>0.05)；与西药组比较,没有明显差异(P>0.05)；与模型组比较,则TC, TG, LDL-C水平明显降低(P<0.05), HDL-C水平明显提高(P<0.05)。模型组,与对照组比较,TC, TG, LDL-C水平明显升高(P<0.05),而HDL-C水平明显降低(P<0.05)；
3.实验结果通过统计学处理之后,发现中药大剂量组,与对照组比较,肝脏HMG-CR以及血清MCP-1, ET-1的水平没有明显差异(P>0.05)；与中药小剂量组比较,肝脏HMG-CR以及血清MCP-1, ET-1的水平没有明显差异(P>0.05)；与西药组比较,则没有明显差异(P>0.05)；与模型组比较,则肝脏HMG-CR以及血清MCP-1, ET-1水平明显降低,有明显差异(P<0.05)。
4.对空白对照组,中药大剂量组,西药组,中药小剂量组,模型组的大鼠血管LOX-1的mRNA的RT-PCR产物进行电泳后。通过对其中心区域的灰度值进行扫描分析,然后分别将对应组别自己的LOX-1的mRNA的电泳产物与自己所属的组别的beta-Actin的mRNA的电泳产物的灰度值进行比较,计算两者之间数值的比值。结果显示,与正常对照组比较,模型组的LOX-1的mRNA的相对含量明显上升(P<0.05)；与模型组的LOX-1的mRNA的相对含量比较,中药大剂量组,西药组,中药小剂量组的LOX-1的相对含量均下降明显(P<0.05),而特别是以中药大剂量组的下降最为明显；
5.显微结构方面主要表现在动脉内膜失去光滑状态,内皮细胞受到损伤,排列失去正常的秩序,内皮细胞间隙增宽,单核巨噬细胞的浸润,泡沫细胞的形成,平滑肌细胞的变形,增生；在超微结构层面则表现为内皮细胞的损伤,结构异常,胞膜失去光滑平整的状态,细胞内线粒体肿胀,粗面内质网减少,细胞胞质显清稀,内皮细胞间隙扩大,可见单核巨噬细胞浸润等异常表现；通过中药小剂量干预后,大鼠血管病变的程度可见明显变轻,且随着温肾方剂量的提高,亚临床甲减大鼠血管病变的情形明显减轻,而且较之西药治疗组而言,还能够体现出其对于纠正亚临床甲减大鼠血管病变的优势。
结论：采取“甲状腺全切+每日皮下注射L-T4”这种造模方法可以成功制备SCH模型大鼠。运用这种方法制备的SCH模型大鼠,外周组织处于低T3的组织甲减状态,而肝组织中的HMG-CoA还原酶的含量偏高,由于肝脏高HMG-CoA还原酶水平以及组织低T3状态导致SCH模型大鼠的高TC, LDL-C尤其是高OX-LDL水平的血脂紊乱状态,从而发生对于血管内皮的脂毒性作用,即对于血管内皮细胞的直接损伤；而这种损伤引起的ET-1, MCP-1等又反过来加重血管病变,形成较为严重的血管病变；通过温肾方干预SCH大鼠后,发现温肾方确实能够改善实验大鼠的SCH状态,提高外周组织T3的利用率,调整血脂紊乱状态,尤其是降低OX-LDL的水平,从而缓解对于血管内皮的直接损伤以及由之引起的继发性血管病变,这种疗效是明显的,而且相较于西药组在改善血管内皮损伤,减轻血管病变方面,中药组尤其是中药大剂量组效果更加突出。这就为在临床上推广运用温肾方提供了动物实验的证据和基础。
Objective:to observe the effect of Wen Shenfang healing the pathological changes of SCH model rats and its blood vessels'da-mage;
Method:select8healthy Wistar rats who are6months old from the whole50rats as the control group; Then make the operation that cut the thyroid off all from the rested rats and inject L-T4to these oprated rats to make sure these rats being with the SCH status. When find all these rats had become into SCH status, separate these rats into4groups—model、TCM (Mediate)、TCM(high)、L-T4group. Then turn drugs into these rats'stomachs for30days.Then
1.Use the chemiluminescence trial to detect the level of the function of all these rats 'Thyroid-FT3, FT4, TSH.
2. Use Toshiba DBA-120type fully automatic biochemistry analyzer to detect the blood fat's concentration of the experimental rats.
3. Detectthe rats' liver tissues 'HMG-CoA reductase and serum MCP-1, ET-1level by Elisa method.
4. Remove the rat the main thoracic aorta 's2cm, then homogenate them, take the clear liquid, extract the total RNA, using the RT-PCR technology to expand gene fragments in vitro, amplifying product through the electrophoresis, through to the electrophoresis photos on grey value for testing, compare the LOX-1mRNA's relative content.
5. Take rat body materials from them after irrigation treatment stomach, remove the rat the thoracic specimens, prepare patho-logical specimens, through the light and electron microscopic for observating experimental rats' thoracic aorta 's microstructure and ultrastructure;
Results:1. The group compared with normal, model rats, serum TSH level increased significantly (P<0.01). Group compared with model, Chinese traditional medicine group TSH level is reduced significantly (p<0.05); TSH leels significantly reduce western medicine group (P<0.05); High dose group of traditional Chinese medicine TSH leels significantly reduce (p<0.05). FT3between groups, FT4level no difference obvious (P>0.05) model group liver TT3content, group compared with normal, have reduced significantly (P<0.05); High in the group, Chinese traditional medicine group, western medicine group TT3content are liver is obviously improve the model group (P<0.05), and especially the Chinese traditional medicine the high group most obvious increase;
2. High dose group of traditional Chinese medicine, compared with controls, plasma TC, TG, LDL-C, hdl-c level no obvious difference (p>0.05);, compared with Chinese traditional medicine group, serum lipid four level no obvious difference (P>0.05); Group compared with western medicine, there was no significant difference (P>0.05); And model group, the comparative plasma TC, TG, LDL-C level reduced significantly (P<0.05), serum levels of HDL-C level obviously improve (P<0.05). Model group, compared with controls, plasma TC, TG, LDL-C level increased significantly (P<0.05), and HDL-C level reduced significantly (P<0.05);
3. The experimental results through the statistics processing, it was found that the high dose group of traditional Chinese medicine, compared with controls, the liver HMG-CR, and serum MCP-1, ET-1level no obvious difference (p>0.05);, compared with Chinese traditional medicine group, the liver HMG-CR, and serum MCP-1, ET-1level no obvious difference (P>0.05); Group compared with western medicine, but no obvious difference (P>0.05); And model group, the comparative liver HMG-CR, and serum MCP-1, ET-1level reduced significantly, and have obvious difference (P<0.05).
4. Of blank control, high dose group of traditional Chinese medicine, western medicine group, Chinese traditional medicine group, the model group rats blood vessels of LOX-1mRNA RT-PCR products after electrophoresis. Through the central region of the scan the grey value analysis, then, will the corresponding group respectively their LOX-1the mRNA products and electrophoresis own groups of beta-Actin mRNA of the electrophoresis of grey value product comparison, between the ratio of numerical calculation. Results show that, compared with the normal control group, the model group LOX-1the relative content of the mRNA rose substantially (P<0.05); And the model group of LOX-1the relative content is the mRNA, high dose group of traditional Chinese medicine, western medicine group, the Chinese traditional medicine group LOX-1the relative content of decreased significantly (P<0.05), and especially in high doses of Chinese traditional medicine group dropped the most obvious;
5. Microscopic structure is mainly manifested in the artery lining losing smoothy state, endothelial cells' damaging, arrangement, losing the normal order of things, the wide gap between endothelial cells, monocyte macrophages infiltrates, and the formation of the foam cells, smooth muscle cells deformation, the hyperplasia; In the ul trastructural level is behaved for endothelial cell injury, structured exception, the film lost smooth level off state in cells, mitochondria swell, rough endoplasmic reticulum reduce, cytoplasm show clear thin, endothelial gap expand, visible mononuclear macrophages, an infiltration performance; Through the Chinese medicine dose after intervention, rats the degree of vascular lesions can be obviously lighter, and with the increase of temperature renal party dose, the clinical JiaJian rats vascular lesions in the case of the apparent ease, and compared with western medicine in the treatment group, also can embody the corrective and clinical JiaJian rats vascular lesions of the slightly advantage. Conclusion:Taking "all thyroid cutness+daily subcutaneous injection L-T40.95ug/100g"-the modeling methods for the preparation of success-can succeed in making up SCH model rats. Using the method of preparation of SCH model rats, peripheral organization in the organization of the state JiaJian low T3, and liver tissue of the HMG-CoA reductase content on the high side, because the liver high HMG-CoA reductase level and low T3state SCH organization in rat models of high TC, LDL-C especially high OX-LDL level of blood lipid disorders, which happen to the fat of toxicity of vascular endothelial function, or for endothelial cell direct damage; And this kind of damage ET-1, MCP-1etc, in turn, aggravating vascular lesions, form relatively serious vascular lesions; The warm renal party intervention SCH rats and find that temperature renal party will really improve experimental rats SCH of state and increase the utilization rate of the week outside organization T3, adjust blood lipid disorders, especially reduce OX-LDL level and rel ieve for the damage and the vascular endothel ial directly caused by the secondary vascular lesions, the curative effect is obvious, and compared with western medicine group, it can improve endothelial injury, reduce vascular lesions.Chinese traditional medicine group especially high dose group of traditional Chinese medicine effect is more outstanding. This is for the wide use of temperature in the clinical renal party to provide evidence of the animal experiment and the foundation. Title:The experimental research for the influence of Wenshen Fang on subclinical hypothyroidism rats 'vascular injury Profession:Internal medicne of TCM Name:Pan Liwen Tutor:Professor Chen Ruquan
方法：将健康6周龄SPF级Wistar大鼠50只随机抽取8只设为正常对照组。而将正常对照组以外的大鼠行“甲状腺全切+术后皮下注射L-T4”法制备亚临床甲减大鼠模型,造模成功后将这些大鼠随机分为模型组,中药小剂量组,西药组,中药大剂量组。然后对此四组的大鼠行连续30天的灌胃治疗,然后
1.采用化学发光法检测大鼠血清甲功三项的含量,采用Elisa法检测肝脏组织TT3的含量；
2.运用东芝DBA-120型全自动生化分析仪对所有实验大鼠的血脂四项(TC、TG、LDL-C、HDL-C)的浓度进行检测；
3.对大鼠的肝组织中HMG-CoA还原酶及血清中MCP-1, ET-1的水平采用Elisa法进行检测；
4.取出大鼠胸主动脉2cm,匀浆,取其上清液,提取总RNA,利用RT-PCR技术进行基因片段的体外扩增,扩增产物通过电泳后,通过对其电泳照片上灰度值进行检测,比较其LOX-1mRNA的相对含量；
5.于灌胃结束后的第二天在实验大鼠身上取材,取出大鼠胸主动脉标本,制备病理标本,通过光镜和电镜观察实验大鼠胸主动脉显微结构与超微结构；
结果：1.与正常组比较,模型组大鼠血清TSH水平明显升高(P<0.01)。与模型组比较,中药小剂量组TSH水平较明显降低(P<0.05)；西药组TSH水平明显降低(P<0.05)；中药大剂量组TSH水平明显降低(P<0.05)。各组之间FT3, FT4水平无明显差异(P<0.05)模型组肝脏TT3含量,与正常组比较,有明显降低(P<0.05)；中药大剂量组,中药小剂量组,西药组肝脏TT3含量均较模型组明显提高(P<0.05),而其中尤以中药大剂量组的提高最为明显；
2.中药大剂量组,与对照组比较,血浆TC, TG, LDL-C, HDL-C水平没有明显差异(P>0.05)；,与中药小剂量组比较,血脂四项的水平没有明显差异(P>0.05)；与西药组比较,没有明显差异(P>0.05)；与模型组比较,则TC, TG, LDL-C水平明显降低(P<0.05), HDL-C水平明显提高(P<0.05)。模型组,与对照组比较,TC, TG, LDL-C水平明显升高(P<0.05),而HDL-C水平明显降低(P<0.05)；
3.实验结果通过统计学处理之后,发现中药大剂量组,与对照组比较,肝脏HMG-CR以及血清MCP-1, ET-1的水平没有明显差异(P>0.05)；与中药小剂量组比较,肝脏HMG-CR以及血清MCP-1, ET-1的水平没有明显差异(P>0.05)；与西药组比较,则没有明显差异(P>0.05)；与模型组比较,则肝脏HMG-CR以及血清MCP-1, ET-1水平明显降低,有明显差异(P<0.05)。
4.对空白对照组,中药大剂量组,西药组,中药小剂量组,模型组的大鼠血管LOX-1的mRNA的RT-PCR产物进行电泳后。通过对其中心区域的灰度值进行扫描分析,然后分别将对应组别自己的LOX-1的mRNA的电泳产物与自己所属的组别的beta-Actin的mRNA的电泳产物的灰度值进行比较,计算两者之间数值的比值。结果显示,与正常对照组比较,模型组的LOX-1的mRNA的相对含量明显上升(P<0.05)；与模型组的LOX-1的mRNA的相对含量比较,中药大剂量组,西药组,中药小剂量组的LOX-1的相对含量均下降明显(P<0.05),而特别是以中药大剂量组的下降最为明显；
5.显微结构方面主要表现在动脉内膜失去光滑状态,内皮细胞受到损伤,排列失去正常的秩序,内皮细胞间隙增宽,单核巨噬细胞的浸润,泡沫细胞的形成,平滑肌细胞的变形,增生；在超微结构层面则表现为内皮细胞的损伤,结构异常,胞膜失去光滑平整的状态,细胞内线粒体肿胀,粗面内质网减少,细胞胞质显清稀,内皮细胞间隙扩大,可见单核巨噬细胞浸润等异常表现；通过中药小剂量干预后,大鼠血管病变的程度可见明显变轻,且随着温肾方剂量的提高,亚临床甲减大鼠血管病变的情形明显减轻,而且较之西药治疗组而言,还能够体现出其对于纠正亚临床甲减大鼠血管病变的优势。
结论：采取“甲状腺全切+每日皮下注射L-T4”这种造模方法可以成功制备SCH模型大鼠。运用这种方法制备的SCH模型大鼠,外周组织处于低T3的组织甲减状态,而肝组织中的HMG-CoA还原酶的含量偏高,由于肝脏高HMG-CoA还原酶水平以及组织低T3状态导致SCH模型大鼠的高TC, LDL-C尤其是高OX-LDL水平的血脂紊乱状态,从而发生对于血管内皮的脂毒性作用,即对于血管内皮细胞的直接损伤；而这种损伤引起的ET-1, MCP-1等又反过来加重血管病变,形成较为严重的血管病变；通过温肾方干预SCH大鼠后,发现温肾方确实能够改善实验大鼠的SCH状态,提高外周组织T3的利用率,调整血脂紊乱状态,尤其是降低OX-LDL的水平,从而缓解对于血管内皮的直接损伤以及由之引起的继发性血管病变,这种疗效是明显的,而且相较于西药组在改善血管内皮损伤,减轻血管病变方面,中药组尤其是中药大剂量组效果更加突出。这就为在临床上推广运用温肾方提供了动物实验的证据和基础。
Objective:to observe the effect of Wen Shenfang healing the pathological changes of SCH model rats and its blood vessels'da-mage;
Method:select8healthy Wistar rats who are6months old from the whole50rats as the control group; Then make the operation that cut the thyroid off all from the rested rats and inject L-T4to these oprated rats to make sure these rats being with the SCH status. When find all these rats had become into SCH status, separate these rats into4groups—model、TCM (Mediate)、TCM(high)、L-T4group. Then turn drugs into these rats'stomachs for30days.Then
1.Use the chemiluminescence trial to detect the level of the function of all these rats 'Thyroid-FT3, FT4, TSH.
2. Use Toshiba DBA-120type fully automatic biochemistry analyzer to detect the blood fat's concentration of the experimental rats.
3. Detectthe rats' liver tissues 'HMG-CoA reductase and serum MCP-1, ET-1level by Elisa method.
4. Remove the rat the main thoracic aorta 's2cm, then homogenate them, take the clear liquid, extract the total RNA, using the RT-PCR technology to expand gene fragments in vitro, amplifying product through the electrophoresis, through to the electrophoresis photos on grey value for testing, compare the LOX-1mRNA's relative content.
5. Take rat body materials from them after irrigation treatment stomach, remove the rat the thoracic specimens, prepare patho-logical specimens, through the light and electron microscopic for observating experimental rats' thoracic aorta 's microstructure and ultrastructure;
Results:1. The group compared with normal, model rats, serum TSH level increased significantly (P<0.01). Group compared with model, Chinese traditional medicine group TSH level is reduced significantly (p<0.05); TSH leels significantly reduce western medicine group (P<0.05); High dose group of traditional Chinese medicine TSH leels significantly reduce (p<0.05). FT3between groups, FT4level no difference obvious (P>0.05) model group liver TT3content, group compared with normal, have reduced significantly (P<0.05); High in the group, Chinese traditional medicine group, western medicine group TT3content are liver is obviously improve the model group (P<0.05), and especially the Chinese traditional medicine the high group most obvious increase;
2. High dose group of traditional Chinese medicine, compared with controls, plasma TC, TG, LDL-C, hdl-c level no obvious difference (p>0.05);, compared with Chinese traditional medicine group, serum lipid four level no obvious difference (P>0.05); Group compared with western medicine, there was no significant difference (P>0.05); And model group, the comparative plasma TC, TG, LDL-C level reduced significantly (P<0.05), serum levels of HDL-C level obviously improve (P<0.05). Model group, compared with controls, plasma TC, TG, LDL-C level increased significantly (P<0.05), and HDL-C level reduced significantly (P<0.05);
3. The experimental results through the statistics processing, it was found that the high dose group of traditional Chinese medicine, compared with controls, the liver HMG-CR, and serum MCP-1, ET-1level no obvious difference (p>0.05);, compared with Chinese traditional medicine group, the liver HMG-CR, and serum MCP-1, ET-1level no obvious difference (P>0.05); Group compared with western medicine, but no obvious difference (P>0.05); And model group, the comparative liver HMG-CR, and serum MCP-1, ET-1level reduced significantly, and have obvious difference (P<0.05).
4. Of blank control, high dose group of traditional Chinese medicine, western medicine group, Chinese traditional medicine group, the model group rats blood vessels of LOX-1mRNA RT-PCR products after electrophoresis. Through the central region of the scan the grey value analysis, then, will the corresponding group respectively their LOX-1the mRNA products and electrophoresis own groups of beta-Actin mRNA of the electrophoresis of grey value product comparison, between the ratio of numerical calculation. Results show that, compared with the normal control group, the model group LOX-1the relative content of the mRNA rose substantially (P<0.05); And the model group of LOX-1the relative content is the mRNA, high dose group of traditional Chinese medicine, western medicine group, the Chinese traditional medicine group LOX-1the relative content of decreased significantly (P<0.05), and especially in high doses of Chinese traditional medicine group dropped the most obvious;
5. Microscopic structure is mainly manifested in the artery lining losing smoothy state, endothelial cells' damaging, arrangement, losing the normal order of things, the wide gap between endothelial cells, monocyte macrophages infiltrates, and the formation of the foam cells, smooth muscle cells deformation, the hyperplasia; In the ul trastructural level is behaved for endothelial cell injury, structured exception, the film lost smooth level off state in cells, mitochondria swell, rough endoplasmic reticulum reduce, cytoplasm show clear thin, endothelial gap expand, visible mononuclear macrophages, an infiltration performance; Through the Chinese medicine dose after intervention, rats the degree of vascular lesions can be obviously lighter, and with the increase of temperature renal party dose, the clinical JiaJian rats vascular lesions in the case of the apparent ease, and compared with western medicine in the treatment group, also can embody the corrective and clinical JiaJian rats vascular lesions of the slightly advantage. Conclusion:Taking "all thyroid cutness+daily subcutaneous injection L-T40.95ug/100g"-the modeling methods for the preparation of success-can succeed in making up SCH model rats. Using the method of preparation of SCH model rats, peripheral organization in the organization of the state JiaJian low T3, and liver tissue of the HMG-CoA reductase content on the high side, because the liver high HMG-CoA reductase level and low T3state SCH organization in rat models of high TC, LDL-C especially high OX-LDL level of blood lipid disorders, which happen to the fat of toxicity of vascular endothelial function, or for endothelial cell direct damage; And this kind of damage ET-1, MCP-1etc, in turn, aggravating vascular lesions, form relatively serious vascular lesions; The warm renal party intervention SCH rats and find that temperature renal party will really improve experimental rats SCH of state and increase the utilization rate of the week outside organization T3, adjust blood lipid disorders, especially reduce OX-LDL level and rel ieve for the damage and the vascular endothel ial directly caused by the secondary vascular lesions, the curative effect is obvious, and compared with western medicine group, it can improve endothelial injury, reduce vascular lesions.Chinese traditional medicine group especially high dose group of traditional Chinese medicine effect is more outstanding. This is for the wide use of temperature in the clinical renal party to provide evidence of the animal experiment and the foundation. Title:The experimental research for the influence of Wenshen Fang on subclinical hypothyroidism rats 'vascular injury Profession:Internal medicne of TCM Name:Pan Liwen Tutor:Professor Chen Ruquan
引文
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