骨髓间充质干细胞联合维生素E对急性肾损伤的治疗研究

发布时间：2019-01-05 08:38

【摘要】：急性肾损伤（Acute kidney injury，AKI）是临床上常见的疾病，可由肾毒性药物、肾脏急性缺血等因素导致。近年来，随着医疗技术的逐步发展，人类多种疾病均得到了有效的治疗，但是，AKI这种疾病的治疗现状尚未得到本质性的改善，其相关的发病率和死亡率甚至有逐年升高的趋势。所以，开发一种新型AKI治疗模式，在临床方面具有着重要的意义。干细胞技术是再生医学研究领域的前沿技术之一，近年来，干细胞治疗手段也为多种疾病提供了新的研究策略。这种干细胞治疗策略以其毒副作用小、疗效显著等因素，受到研究人员的广泛认可，其治疗效果也明显优于传统的药物治疗模式。特别是骨髓间充质干细胞（bone marrow derived mesenchymal stem cells，BMSCs），因其取材、培养等方面的可操作性，在多种疾病的治疗方面均有着一定的临床应用，在AKI治疗方面，BMSCs也具有一定的研究基础。在本课题中，我们采用庆大霉素损伤的方法制备肾小管上皮细胞（renal tubularepithelial cells，RTECs）损伤模型和大鼠AKI模型，从抑制损伤因素和修复受损组织的角度，采用BMSCs联合维生素E的方法，在体内外水平上对损伤进行治疗。结果显示：在庆大霉素损伤的情况下，BMSCs和维生素E均可以起到改善RTECs活力的作用，二者联合时会起到更优越的效果（P＜0.05）。在体内治疗过程中，BMSC（s3.3×106cells/kg）联合维生素E（80mg/kg）的治疗模式的AKI大鼠在血肌酐及尿素氮的改善方面，具有着最佳的治疗效果。在病理学改变方面，，联合治疗组的肾脏组织在肾小管细胞坏死、变形及肿胀方面显著缓解，透射电镜下也可见RTECs胞浆中的内质网等细胞器显著恢复。细胞凋亡基因Caspase3、Caspase9和Fas在AKI模型组均显著上调，在各治疗组中均有一定的下调趋势，其中，联合治疗模式对于Caspase9和Fas的抑制，显著优于单一治疗方法。进一步分析表明：这种联合治疗方法的优势，可能是BMSCs与维生素E单独作用的结果，二者之间并不存在明显的协同作用关系。综上所述，本课题初步表明：BMSCs联合维生素E对AKI具有一定的治疗效果，而且治疗作用优于单一的治疗模式。所以，本课题不仅开发了一种针对于AKI的新型生物治疗模式，基于BMSCs的低毒副作用和维生素E的经济性，该方法也具有着较大的临床应用价值。
[Abstract]:Acute renal injury (Acute kidney injury,AKI) is a common clinical disease, which can be caused by nephrotoxic drugs, acute renal ischemia and other factors. In recent years, with the gradual development of medical technology, a variety of human diseases have been effectively treated, but the treatment of AKI disease has not yet been substantially improved. Its related morbidity and mortality even increased year by year. Therefore, it is of great significance to develop a new model of AKI therapy in clinic. Stem cell technology is one of the leading technologies in regenerative medicine. In recent years, stem cell therapy has provided new research strategies for many diseases. The stem cell therapy strategy has been widely accepted by researchers because of its small side effects and significant curative effect, and its therapeutic effect is obviously superior to the traditional drug treatment mode. Especially the bone marrow mesenchymal stem cell (bone marrow derived mesenchymal stem cells,BMSCs), because of its maneuverability in the aspects of material, culture and so on, has certain clinical application in the treatment of many kinds of diseases, and in the aspect of AKI treatment. BMSCs also has a certain research foundation. In this study, gentamicin was used to prepare renal tubular epithelial cell (renal tubularepithelial cells,RTECs) injury model and rat AKI model. From the point of view of inhibiting injury factors and repairing damaged tissue, BMSCs combined with vitamin E was used. The injury was treated in vivo and in vitro. The results showed that both BMSCs and vitamin E could improve the activity of RTECs when gentamicin was damaged, and the combination of them had a better effect (P < 0. 05). In vivo treatment, AKI rats treated with, BMSC (s 3.3 脳 106cells/kg combined with vitamin E (80mg/kg) had the best therapeutic effect in improving serum creatinine and urea nitrogen. In the pathological changes, the renal tissue in the combined treatment group significantly alleviated the necrosis, deformation and swelling of renal tubule cells, and the endoplasmic reticulum in the cytoplasm of RTECs recovered significantly under transmission electron microscope. The apoptotic gene Caspase3,Caspase9 and Fas were significantly up-regulated in the AKI model group and down-regulated in each treatment group. The combined treatment mode was superior to the single treatment method in inhibiting Caspase9 and Fas. Further analysis showed that the advantages of this combination therapy may be the result of BMSCs and vitamin E alone, and there is no obvious synergistic relationship between them. To sum up, this subject preliminarily indicated that BMSCs combined with vitamin E had a certain therapeutic effect on AKI, and the therapeutic effect was superior to that of single treatment mode. Therefore, this paper not only develops a new biotherapy model for AKI, but also has great clinical application value, which is based on the low toxicity and side effect of BMSCs and the economy of vitamin E.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R692.5

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