Antifibrotic action of pirfenidone and prednisolone: Different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis
Antifibrotic action of pirfenidone and prednisolone: Different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis
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DOI：
10.1016/j.ejphar.2008.06.046
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发表时间：
2008-08-20
影响因子：
5
通讯作者：
Arimura, Akinori
中科院分区：
文献类型：
--
作者：
Oku, Hisashi;Shimizu, Toshikatsu;Arimura, Akinori
吡非尼酮是一种广谱抗纤维化药物，已知对某些纤维化疾病模型有效，目前正在对特发性肺纤维化患者进行临床试验。以强的松龙为参照物，从蛋白水平探讨吡非尼酮对博莱霉素性小鼠肺纤维化的抗纤维化作用及其对多种肺细胞因子的调节作用。吡非尼酮可减轻博莱霉素性肺纤维化，最小有效剂量为30 mg/kg/d，tid。从肺组织羟脯氨酸含量分析。吡非尼酮(30,100 mg/kg/d)和强的松龙(3，15 mg/kg/d，qd)。抑制肺炎性水肿；然而，强的松龙不能抑制肺纤维化，只有吡非尼酮才能显著抑制肺纤维化。吡非尼酮和强的松龙均能抑制博莱霉素诱导的肺组织IL-1β、IL-6、IL-12p40和单核细胞趋化蛋白-1水平的升高。另一方面，吡非尼酮可阻止博莱霉素引起的肺组织干扰素-γ水平下降，而强的松龙则无此作用。此外，吡非尼酮可抑制肺组织碱性成纤维细胞生长因子和转化生长因子-β1水平的升高，而强的松龙则无此作用。肺基质细胞衍生因子(SDF)-1α和IL-18的升高也受到抑制。提示吡非尼酮在博莱霉素诱导的小鼠肺纤维化形成过程中，通过调节肺组织中干扰素-γ、碱性成纤维细胞生长因子和转化生长因子-β1的水平发挥抗纤维化作用。其对SDF-1α和IL-18水平的影响也可能与吡非尼酮的抗纤维化作用有关。(C)2008爱思唯尔B.V.保留所有权利。
Pirfenidone, a broad-spectrum antifibrotic agent, is known to have efficacy in certain fibrotic disease models, and is under clinical trials in patients with idiopathic pulmonary fibrosis. We investigated the antifibrotic effect of pirfenidone, and its regulatory effect on various pulmonary cytokines, in bleomycin-induced lung fibrosis in mice at the protein level, using prednisolone as a reference agent. Pirfenidone attenuated the bleomycin-induced pulmonary fibrosis at a minimum effective dose of 30 mg/kg/day t.i.d. from the analysis of lung hydroxyproline content. Both pirfenidone (30, 100 mg/kg/day t.i.d) and prednisolone (3,15 mg/kg/day q.d.) suppressed lung inflammatory edema; however, prednisolone failed to suppress pulmonary fibrosis, which was significantly suppressed only by pirfenidone. Both pirfenidone and prednisolone suppressed the increase in lung interleukin (IL)-1 beta, IL-6, IL-12p40 and monocyte chemoattractant protein (MCP)-1 levels induced by bleomycin. On the other hand, pirfenidone prevented the bleomycin-induced decrease in lung interferon (IFN)-gamma levels, while prednisolone had no such effect. Furthermore, pirfenidone suppressed elevation of lung basic-fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta 1 levels, but prednisolone had no such effect. The increases in lung stroma cell derived factor (SDF)-1 alpha and IL-18 were also suppressed. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of lung IFN-gamma, bFGF and TGF-beta 1 levels during the development of bleomycin-induced pulmonary fibrosis in mice. The effect on SDF-1 alpha and IL-18 levels may also be related to the antifibrotic effects of pirfenidone. (C) 2008 Elsevier B.V. All rights reserved.