Role of α1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice
Role of α1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice
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DOI：
10.1164/rccm.200702-178oc
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发表时间：
2007-12-15
影响因子：
24.7
通讯作者：
Sone, Saburo
中科院分区：
文献类型：
--
作者：
Azuma, Momoyo;Nishioka, Yasuhiko;Sone, Saburo
原理：伊马替尼是一种血小板衍生生长因子受体的抑制剂。我们已经报道，伊马替尼治疗可以抑制博莱霉素所致的小鼠肺纤维化。目的：为了阐明伊马替尼延迟给药后无抗纤维化作用的原因，我们将研究重点放在与伊马替尼结合并介导耐药的酸性糖蛋白(AGP)上。方法：采用放射免疫扩散法检测特发性肺纤维化小鼠和患者血清中AGP浓度。通过检测肺成纤维细胞的生长情况来评价AGP的体外作用。我们研究了红霉素(EM)或克拉霉素(CAM)对博莱霉素诱导的小鼠肺纤维化的联合作用。测量和主要结果：加入AGP可抑制伊马替尼介导的成纤维细胞生长。然而，EM或CAM处理可恢复伊马替尼的生长抑制作用。博莱霉素组小鼠血清和肺组织匀浆中AGP水平升高，第14天达到高峰。伊马替尼在第15天开始治疗时不能减轻肺纤维化，而伊马替尼和EM或CAM联合应用可通过抑制体内成纤维细胞的生长而显著减少纤维化的形成。结论：AGP是调节伊马替尼预防小鼠肺纤维化作用的重要调节因子，伊马替尼与EM或CAM联合治疗可能对肺纤维化有一定的治疗作用。
Rationale: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-incluced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect.Objectives: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on (xi-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance.Methods: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice.Measurements and Main Results: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects.Conclusions: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.