Kiberd B A, Young I D
Department of Medicine, Queen's University, Kingston, Ontario, Canada.
J Lab Clin Med. 1994 Oct;124(4):496-506.
The effects of methylprednisolone and cyclophosphamide were examined in a murine model of lupus nephritis (MRL-1pr/1pr). Animals were assigned to four groups at 12 weeks of age. Mice in the control group received intraperitoneal saline solution either daily or weekly. Animals in the low-dose methylprednisolone (MPLD) group received 6 mg/kg/day intraperitoneal methylprednisolone; those in the high-dose methylprednisolone (MPHD) group received 12 mg/kg/day intraperitoneal methylprednisolone. Animals in the cyclophosphamide group received 50 mg/kg/wk intraperitoneal cyclophosphamide. Animals surviving to 24 weeks were examined. MPHD and cyclophosphamide treatments were associated with maintenance of normal glomerular filtration rates and the development of only minimal proteinuria. However, detailed morphometric evaluation of the glomerulus revealed glomerular enlargement and mesangial matrix expansion in both groups. Unlike MPHD-treated mice, cyclophosphamide-treated animals demonstrated a marked reduction in the number of osmophilic dense deposits along the glomerular capillary walls. MPLD had little effect on function, despite significant reductions in cell proliferation and anti-double-strand DNA antibodies. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were dramatically increased in plasma of control animals. Treatment with methylprednisolone and cyclophosphamide dramatically reduced TNF-alpha but not IL-6. Treatment also reduced renal IL-1 beta, TNF-alpha and transforming growth factor-beta mRNA levels compared with untreated mice. Despite minimal serologic activity and preservation of renal function, neither cyclophosphamide nor methylprednisolone was able to completely suppress disease activity, as measured by increased cytokine production and glomerular structural injury. The inability of treatment to reduce IL-6 levels may explain the resistance to treatment in this model.
在狼疮性肾炎（MRL-1pr/1pr）小鼠模型中研究了甲基强的松龙和环磷酰胺的作用。动物在12周龄时被分为四组。对照组小鼠每天或每周接受腹腔注射生理盐水。低剂量甲基强的松龙（MPLD）组的动物接受6mg/kg/天腹腔注射甲基强的松龙；高剂量甲基强的松龙（MPHD）组的动物接受12mg/kg/天腹腔注射甲基强的松龙。环磷酰胺组的动物接受50mg/kg/周腹腔注射环磷酰胺。对存活至24周的动物进行检查。MPHD和环磷酰胺治疗与维持正常肾小球滤过率以及仅出现微量蛋白尿有关。然而，对肾小球的详细形态计量学评估显示两组均有肾小球增大和系膜基质扩张。与MPHD治疗的小鼠不同，环磷酰胺治疗的动物沿肾小球毛细血管壁的嗜锇致密沉积物数量明显减少。MPLD对功能影响不大，尽管细胞增殖和抗双链DNA抗体显著降低。对照组动物血浆中的肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平显著升高。甲基强的松龙和环磷酰胺治疗显著降低了TNF-α，但未降低IL-6。与未治疗的小鼠相比，治疗还降低了肾脏IL-1β、TNF-α和转化生长因子-β的mRNA水平。尽管血清学活性 minimal 且肾功能得以保留，但通过细胞因子产生增加和肾小球结构损伤衡量，环磷酰胺和甲基强的松龙均不能完全抑制疾病活性。治疗无法降低IL-6水平可能解释了该模型中对治疗的抵抗。
