Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice
Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice
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DOI：
10.1016/s0378-4274(96)03845-3
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发表时间：
1997-02-07
影响因子：
3.5
通讯作者：
Margolin, SB
中科院分区：
文献类型：
--
作者：
Kehrer, JP;Margolin, SB
肺纤维化特征性的过量或异常胶原蛋白的沉积可破坏气体交换，导致严重的呼吸障碍。目前还没有有效的药物可用于抑制纤维化过程。吡非尼酮（5-甲基-1-苯基-2-（IH）-吡啶酮）是一种研究药物，当以饲料的0.5%（w/w）给药时，可减少经博莱霉素肠内给药仓鼠肺纤维化的组织学和生化证据。在用200 mg/kg环磷酰胺（CP）腹膜内处理的小鼠中研究了吡非尼酮对由全身给药的药剂引发的肺纤维化的有效性。从CP后1天开始，对对照组和给药组动物饲喂含0.277%（w/w）吡非尼酮的饲料。尽管CP给药小鼠在给药后第一天出现厌食，但它们在20天内摄入的平均吡非尼酮剂量高于盐水给药对照小鼠（分别为717+/-44 vs 564+/-30 mg/kg/天）。与仅用CP处理的小鼠相比，用CP加吡非尼酮处理后21天的总肺羟脯氨酸含量（纤维化指数）显著更低。尽管在CP处理的小鼠中，吡非尼酮未显著降低显微镜下肺纤维化评分，但纤维化的总体发生率显著降低。在组织学上，用CP处理的小鼠显示纤维化，而用CP加吡非尼酮处理的小鼠表现出较少的异常。CP处理后9天，肺组织羟脯氨酸合成速率显着升高。该发生率不受吡非尼酮治疗的影响。总体而言，这些数据支持吡非尼酮对CP诱导的小鼠肺纤维化的抗纤维化作用。其作用机制尚不清楚，但似乎与抑制胶原蛋白合成无关。(C)1997 Elsevier Science爱尔兰有限公司
The deposition of excess or abnormal collagen characteristic of pulmonary fibrosis can disrupt gas exchange resulting in severe respiratory impairment. There currently are no effective pharmacologic agents available that inhibit the fibrotic process. Pirfenidone (5-methyl-1-phenyl-2-(IH)-pyridone) is an investigational drug that, when administered at 0.5% (w/w) of the diet, decreases both histologic and biochemical evidence of lung fibrosis in hamsters treated intratracheally with bleomycin. The effectiveness of pirfenidone against lung fibrosis initiated by a systemically administered agent was investigated in mice treated intraperitoneally with 200 mg/kg cyclophosphamide (CP). Control and treated animals were fed a diet containing 0.277% (w/w) pirfenidone beginning 1 day after CP. Despite anorexia in the CP-treated mice the first day after treatment, they ingested a greater average pirfenidone dose over 20 days than saline-treated control mice (717+/-44 versus 564+/-30 mg/kg per day, respectively). Total lung hydroxyproline content, an index of fibrosis, was significantly lower 21 days after treatment with CP plus pirfenidone as compared to mice treated with CP alone. Although microscopic lung fibrosis scores were not significantly decreased by pirfenidone in CP-treated mice, the overall incidence of fibrosis was significantly decreased. Histologically, mice treated with CP showed fibrosis while mice treated with CP plus pirfenidone exhibited fewer abnormalities. The rate of hydroxyproline synthesis by lung tissue 9 days after treatment with CP was significantly elevated. This rate was not affected by pirfenidone treatment. Overall, these data support an antifibrotic effect of pirfenidone against CP-induced lung fibrosis in mice. The mechanism of its effect is not known, but appears to be unrelated to an inhibition of collagen synthesis. (C) 1997 Elsevier Science Ireland Ltd.