Huber S, Bruns C J, Schmid G, Hermann P C, Conrad C, Niess H, Huss R, Graeb C, Jauch K-W, Heeschen C, Guba M
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Kidney Int. 2007 Apr;71(8):771-7. doi: 10.1038/sj.ki.5002112. Epub 2007 Feb 14.
Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigeltrade mark lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.
淋巴并发症是肾移植中基于雷帕霉素哺乳动物靶点（mTOR）抑制剂的免疫抑制常见的副作用。因此，我们研究了mTOR抑制剂雷帕霉素除了其已知的抗血管生成作用外，是否也会阻碍再生性淋巴管生成。在小鼠皮瓣模型中，雷帕霉素损害了手术切口处淋巴液流动的恢复，导致这些动物伤口水肿持续时间延长。重要的是，雷帕霉素的抗淋巴管生成作用与对伤口愈合的一般抑制无关，这在体内基质胶淋巴管生成试验和淋巴管瘤模型中得到了证实。低至1 ng/ml的雷帕霉素浓度分别在体外有效抑制了分离的人淋巴管内皮细胞（LEC）的血管内皮生长因子（VEGF）-C驱动的增殖和迁移。从机制上讲，mTOR抑制通过mTOR损害LEC中VEGF-A以及VEGF-C向p70S6激酶的下游信号传导。总之，我们提供了大量实验证据证明mTOR抑制具有抗淋巴管生成活性，这表明应避免在组织损伤后早期使用mTOR抑制剂。相反，雷帕霉素及其衍生物的抗淋巴管生成特性可能分别为预防和治疗恶性肿瘤提供治疗价值。
