Ryffel B, Foxwell B M, Gee A, Greiner B, Woerly G, Mihatsch M J
Preclinical Research, Sandoz Ltd., Basel, Switzerland.
Transplantation. 1988 Aug;46(2 Suppl):90S-96S. doi: 10.1097/00007890-198808001-00017.
Although cyclosporine has high specificity for the immune system, immunosuppressive therapy with CsA is often complicated by nephrotoxicity. The main morphologic targets of CsA nephrotoxicity include the tubular epithelial and endothelial cells. These cells were investigated in vitro. CsA caused a dose- and time-dependent inhibition of cell growth, vacuolization and fatty change in adherent cells, detachment, and cell death. Inhibition of 3H-TdR incorporation in cells of both tubular epithelial and endothelial origin occurred between 3 microM and 10 microM. Electron microscopy studies revealed cellular swelling, dilatation of the endoplasmic reticulum, and the presence of lipid droplets and giant mitochondria. The content of the main CsA-binding protein, cyclophilin, in these cell-lines was 5-10 micrograms/mg protein and did not differ in various cell lines, including T cells. Immunohistochemistry using rabbit anticyclophilin antibody revealed diffuse distribution of cyclophilin in the cytosol, nuclear membrane, and nucleolus. Whereas lymphoid cell functions are inhibited at 10-100 nM, CsA had no effect on tubular epithelial and endothelial cells at these concentrations. At concentrations of 3-10 microM, CsA caused growth inhibition and cytotoxicity on cells of lymphoid and nonlymphoid origin. Present evidence shows little, if any, relationship of side-effects to the mode of action of CsA.
尽管环孢素对免疫系统具有高度特异性，但使用环孢素进行免疫抑制治疗常伴有肾毒性并发症。环孢素肾毒性的主要形态学靶点包括肾小管上皮细胞和内皮细胞。对这些细胞进行了体外研究。环孢素导致贴壁细胞出现剂量和时间依赖性的细胞生长抑制、空泡化和脂肪变性、细胞脱落及细胞死亡。在3微摩尔/升至10微摩尔/升之间，肾小管上皮细胞和内皮细胞来源的细胞中3H-胸腺嘧啶核苷掺入受到抑制。电子显微镜研究显示细胞肿胀、内质网扩张以及脂滴和巨型线粒体的存在。这些细胞系中环孢素主要结合蛋白亲环蛋白的含量为5 - 10微克/毫克蛋白质，在包括T细胞在内的各种细胞系中并无差异。使用兔抗亲环蛋白抗体的免疫组织化学显示亲环蛋白在细胞质、核膜和核仁中呈弥漫性分布。虽然在10 - 100纳摩尔/升时淋巴细胞功能受到抑制，但在此浓度下环孢素对肾小管上皮细胞和内皮细胞无影响。在3 - 10微摩尔/升浓度下，环孢素对淋巴细胞和非淋巴细胞来源的细胞均有生长抑制和细胞毒性作用。目前的证据表明，副作用与环孢素的作用方式之间几乎没有关系（如果有关系的话也很小）。
