Cheng J, Zhou L, Jiang J W, Qin Y S, Xie H Y, Feng X W, Gao F, Zheng S S
Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, and Key Laboratory of Organ Transplantation, Zhejiang Province, Division of Hepatobiliary Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Eur Surg Res. 2010;44(1):43-51. doi: 10.1159/000264602. Epub 2009 Dec 7.
Acute rejection (AR) after liver transplantation is a cell-mediated immune response that takes place within the allograft and results in graft dysfunction and failure, but the molecular mechanisms about hepatocyte dysfunction remain poorly understood. Here we characterized global protein expression changes in liver allograft during AR.
The effect of an alloantigen-dependent immunological response was evaluated by syngeneic and allogeneic rat orthotopic liver transplantation (OLT). Using a combination of two-dimensional gel electrophoresis and mass spectrometry, we identified 18 differentially expressed proteins in AR allograft compared with matched tolerance allograft. Serum chemistry and allograft histology were determined.
Allogeneic OLT recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allograft compared with syngeneic OLT. 18 protein expressions altered by AR play important roles in metabolism, oxidative stress defense, signal transduction, biotransformation and transport. Decreased expression of protein disulfide isomerase in AR allograft was confirmed by Western blotting and immunohistochemistry.
This study uncovered new mechanistic insights into graft dysfunction in AR of liver allograft. Several significantly altered protein expressions act coordinately in hepatocyte dysfunction by depressed energy, enhanced oxidative stress-induced molecular damage and restrained biotransformation. The present findings may open new avenues for the understanding and prevention of graft dysfunction and failure during AR.
肝移植后的急性排斥反应（AR）是一种发生在同种异体移植物内的细胞介导免疫反应，可导致移植物功能障碍和衰竭，但关于肝细胞功能障碍的分子机制仍知之甚少。在此，我们对AR期间肝同种异体移植物中的整体蛋白质表达变化进行了表征。
通过同基因和异基因大鼠原位肝移植（OLT）评估同种异体抗原依赖性免疫反应的效果。结合二维凝胶电泳和质谱分析，我们鉴定出与匹配的耐受同种异体移植物相比，AR同种异体移植物中有18种差异表达的蛋白质。测定了血清生化指标和同种异体移植物组织学。
与同基因OLT相比，异基因OLT受者的肝损伤标志物血浆水平升高，肝同种异体移植物中出现进行性门静脉和静脉炎症以及细胞浸润。AR改变的18种蛋白质表达在代谢、氧化应激防御、信号转导、生物转化和转运中起重要作用。通过蛋白质免疫印迹和免疫组织化学证实了AR同种异体移植物中蛋白质二硫键异构酶的表达降低。
本研究揭示了肝同种异体移植AR中移植物功能障碍的新机制。几种显著改变的蛋白质表达通过能量降低、氧化应激诱导的分子损伤增强和生物转化受限在肝细胞功能障碍中协同作用。目前的研究结果可能为理解和预防AR期间的移植物功能障碍和衰竭开辟新途径。
