自体骨髓干细胞移植与归元方联用治疗急慢性肝损伤实验研究

吴理茂,李连达,刘红,宁可永,李贻奎

中国工程科学 ›› 2004, Vol. 6 ›› Issue (7) : 34 -42.

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中国工程科学 ›› 2004, Vol. 6 ›› Issue (7) : 34 -42.
学术论文

自体骨髓干细胞移植与归元方联用治疗急慢性肝损伤实验研究

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Studies of the Guiyuan Fang and Autologous Bone Marrow Stem Cells Transplantation on Hepatic Injury and Fibrosis

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研究中药归元方与自体骨髓干细胞移植对急慢性肝损伤的治疗作用。研究方法:用肝脏局部注射乙醇的方法复制急性局限性肝损伤模型,复合因素(CCl4、乙醇、高脂、低蛋白)刺激复制大鼠肝纤维化模型,通过定量组织学、肝功能检查、免疫组化、肝组织羟脯氨酸含量、损伤或纤维区骨髓干细胞观察等综合评价中药、自体骨髓干细胞移植及两者合用的疗效。结果:归元方与自体骨髓干细胞移植可减小肝损伤区域,改善肝功能,使纤维肝组织表达μPA增强,降低血清ALT,AST,PCⅢ,HA和肝组织羟脯氨酸的含量,改善肝组织肝纤维化评分,骨髓干细胞能在肝损伤、肝纤维化形成环境中存活、增殖,并向肝细胞分化,表达肝脏特异的角蛋白CK18。结论:归元方与自体骨髓干细胞移植对急慢性肝损伤有明确的治疗作用,两者合用可优势互补,协同增效。临床上有良好的应用前景。

Abstract

Objective To study the anti-fibrotic and anti-injurious activities of TCM and autologous bone marrow stem cells transplantation. Methods Acute localized liver injury model was induced in rabbits by injecting ethanol locally, and the liver fibrosis models were reproduced by complex factors (high lipid, low protein, alcohol, CCl4). Liver function was assessed by measurement ALT, AST, TP, ALB, and GST. The necrotic areas were measured by pathological analytic system, and the concentrations of serum of PC III , HA in serum were measured by radioimmunoassay. Histopathological changes and degrees of fibrosis, hydroxyproline content in the hepatic tissues were assessed also. /mPA, CK-18, and BrdU - labeled transplanted cells were determined by immunohistochemical staining. Results In the acute liver injury experiment, the reduction of serum GST levels was remarkable in all treated groups, compared with the model group (P<0.05 ). The necrotic regions of the treated groups decrease significantly, compared to model group ( P<0.01). In the inflammatory regions of transplanted rabbits many Brdu-labeled cells were easily observed, most transplanted cells were predominantly in clusters of 1~3 cells each. Part of the cells exhibit the morphology of hepatocyte or bile duct epithelial cells. During liver fibrous experiment, the serum ALT and AST values were reduced significantly in the treated rats (P<0.01), serum TP, ALB, A/G levels were increased in all animals receiving treatment (P<0.01 or 0.05), the serum PC ID , HA levels were also reduced remarkably (P<0.01). Determination of tissue hydroxyproline content confirmed the histological studies, showing a net reduction in total collagen levels. The normal liver tissues showed very weak /xPA expression, and Guiyuan Fang caused a marked increase of /uPA expression in the livers in a dose-dependent manner. The fiPA expression in the autologous BMSCs transplantation group and Guiyuan Fang plus autologous BMSCs transplantation group were the strongest. Double immunohistochemical staining showed the BrdU-labeled cells were fully integrated in the liver parenchyma, along with expression of cytokeratin-18,the liver epithelial specific marker. Some BMSCs have differentiated into hepatocytes or endothelial cells. Conclusion The bone marrow stem cells survive, proliferate, and differentiate in the fibrotic and injurious environment. TCM synergize with bone marrow stem cells to improve liver function, to protect hepatocytes from toxicant, to promote protein synthesis, and to provide a good environment for hepatocyte function. These findings establish the basis for further analysis of BMSCs transplantation in acute and chronic liver diseases.

关键词

归元方 / 骨髓干细胞 / 自体移植 / 肝损伤 / 肝纤维化

Key words

bone marrow stem cells / autologous transplantation / liver injury / liver fibrosis / guiyuan fang

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吴理茂,李连达,刘红,宁可永,李贻奎 自体骨髓干细胞移植与归元方联用治疗急慢性肝损伤实验研究[J]. 中国工程科学, 2004, 6(7): 34-42 DOI:

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