Department of Urology, Charité Universitaetsmedizin Berlin, Berlin, Germany.
Transplantation. 2010 Feb 27;89(4):402-8. doi: 10.1097/TP.0b013e3181caa499.
Fingolimod (FTY720) is a potent agonist of sphingosine 1 phosphate receptors and thereby interferes with lymphocyte trafficking. We previously showed that FTY720 protects from mild preservation reperfusion injury induced by 4 hr of cold ischemia. The purpose of this study was to explore the role of FTY720 in ischemic injury and regeneration using a clinically relevant rat renal transplant model with 24 hr of cold ischemia.
Donor kidneys were cold stored in the University of Wisconsin solution for 24 hr before transplantation into bilaterally nephrectomized syngeneic recipients (n=6 per group), which received 0.5 mg/kg/d FTY720 or vehicle through oral gavage. Grafts were harvested 2 or 7 days posttransplantation. Renal tissue was examined histologically, stained for apoptosis, proliferation, inflammatory cell infiltrates, and studied for transforming growth factor-beta, and tumor necrosis factor-alpha expression. Rat proximal tubular cells were incubated with 0.1 to 30 micromol/L of phosphorylated FTY720 to test for in vitro cytopathic effects.
FTY720 induced peripheral lymphopenia and significantly reduced intragraft CD3 and ED1 infiltrates. Acute tubular damage scores and graft function were not influenced by FTY720. Tubular apoptosis was significantly reduced, whereas the number of proliferating cell nuclear antigen-positive tubular cells were markedly increased. FTY720 attenuated renal tumor necrosis factor-alpha and transforming growth factor-beta expression. In vitro, pharmacologic concentrations up to 1 micromol/L of phosphorylated FTY720 did not affect tubular cell viability.
FTY720 confers tubular epithelial protection in the presence of severe preservation reperfusion injury. Beneficial effects may in part be due to reduction in cell-mediated immune mechanisms. Furthermore, FTY720 could be helpful in patients with delayed graft function.
芬戈莫德（FTY720）是一种有效的鞘氨醇 1 磷酸受体激动剂，从而干扰淋巴细胞的迁移。我们先前表明，FTY720 可防止由 4 小时冷缺血引起的轻度保存再灌注损伤。本研究的目的是使用临床相关的大鼠肾移植模型（冷缺血 24 小时）探索 FTY720 在缺血性损伤和再生中的作用。
供肾在威斯康星大学溶液中冷保存 24 小时，然后移植到双侧肾切除的同基因受体中（每组 6 只），受体通过口服灌胃接受 0.5mg/kg/d FTY720 或载体。移植后 2 或 7 天收获移植物。对肾组织进行组织学检查，对凋亡、增殖、炎症细胞浸润进行染色，并研究转化生长因子-β和肿瘤坏死因子-α的表达。将大鼠近端肾小管细胞与 0.1 至 30 微摩尔/升的磷酸化 FTY720 孵育，以测试体外细胞病变效应。
FTY720 诱导外周血淋巴细胞减少，并显著减少移植肾内 CD3 和 ED1 浸润。FTY720 对急性肾小管损伤评分和移植物功能没有影响。肾小管凋亡明显减少，而增殖细胞核抗原阳性肾小管细胞的数量明显增加。FTY720 下调肾肿瘤坏死因子-α和转化生长因子-β的表达。体外，高达 1 微摩尔/升的磷酸化 FTY720 的药理浓度不影响肾小管细胞活力。
FTY720 在严重保存再灌注损伤存在的情况下赋予肾小管上皮保护作用。有益作用部分可能是由于细胞介导的免疫机制减少。此外，FTY720 可能对延迟移植物功能有帮助。
