【摘要】：急性腎損傷（Acute kidney injury，AKI）是臨床上常見的疾病，可由腎毒性藥物、腎臟急性缺血等因素導致。近年來，隨著醫(yī)療技術的逐步發(fā)展，人類多種疾病均得到了有效的治療，但是，AKI這種疾病的治療現(xiàn)狀尚未得到本質性的改善，其相關的發(fā)病率和死亡率甚至有逐年升高的趨勢。所以，開發(fā)一種新型AKI治療模式，在臨床方面具有著重要的意義。 干細胞技術是再生醫(yī)學研究領域的前沿技術之一，近年來，干細胞治療手段也為多種疾病提供了新的研究策略。這種干細胞治療策略以其毒副作用小、療效顯著等因素，受到研究人員的廣泛認可，其治療效果也明顯優(yōu)于傳統(tǒng)的藥物治療模式。特別是骨髓間充質干細胞（bone marrow derived mesenchymal stem cells，BMSCs），因其取材、培養(yǎng)等方面的可操作性，在多種疾病的治療方面均有著一定的臨床應用，在AKI治療方面，BMSCs也具有一定的研究基礎。 在本課題中，我們采用慶大霉素損傷的方法制備腎小管上皮細胞（renal tubularepithelial cells，RTECs）損傷模型和大鼠AKI模型，從抑制損傷因素和修復受損組織的角度，采用BMSCs聯(lián)合維生素E的方法，在體內外水平上對損傷進行治療。結果顯示：在慶大霉素損傷的情況下，BMSCs和維生素E均可以起到改善RTECs活力的作用，二者聯(lián)合時會起到更優(yōu)越的效果（P＜0.05）。在體內治療過程中，BMSC（s3.3×106cells/kg）聯(lián)合維生素E（80mg/kg）的治療模式的AKI大鼠在血肌酐及尿素氮的改善方面，具有著最佳的治療效果。在病理學改變方面，，聯(lián)合治療組的腎臟組織在腎小管細胞壞死、變形及腫脹方面顯著緩解，透射電鏡下也可見RTECs胞漿中的內質網等細胞器顯著恢復。細胞凋亡基因Caspase3、Caspase9和Fas在AKI模型組均顯著上調，在各治療組中均有一定的下調趨勢，其中，聯(lián)合治療模式對于Caspase9和Fas的抑制，顯著優(yōu)于單一治療方法。進一步分析表明：這種聯(lián)合治療方法的優(yōu)勢，可能是BMSCs與維生素E單獨作用的結果，二者之間并不存在明顯的協(xié)同作用關系。 綜上所述，本課題初步表明：BMSCs聯(lián)合維生素E對AKI具有一定的治療效果，而且治療作用優(yōu)于單一的治療模式。所以，本課題不僅開發(fā)了一種針對于AKI的新型生物治療模式，基于BMSCs的低毒副作用和維生素E的經濟性，該方法也具有著較大的臨床應用價值。
[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.
【學位授予單位】：吉林大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R692.5

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