Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis
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DOI：
10.1002/art.22314
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发表时间：
2007-01-01
影响因子：
--
通讯作者：
Distler, Oliver
中科院分区：
文献类型：
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作者：
Distler, Joerg H. W.;Juengel, Astrid;Distler, Oliver
客观的。甲磺酸伊马替尼是一种临床耐受性良好的小分子抑制剂，对转化生长因子 13 (TGF beta) 和血小板衍生生长因子 (PDGF) 途径发挥选择性双重抑制作用。本研究旨在测试甲磺酸伊马替尼作为抗纤维化药物治疗系统性硬化症 (SSc) 皮肤纤维化的潜在用途。方法。通过实时聚合酶链反应、蛋白质印迹和 Sircol 胶原测定分析 SSc 和正常真皮成纤维细胞中细胞外基质 (ECM) 蛋白的表达。用MTT测定评估增殖能力。通过线粒体膜电位和膜联蛋白V/碘化丙啶染色分析细胞活力。使用博来霉素诱导的实验性真皮纤维化来评估甲磺酸伊马替尼的体内抗纤维化作用。结果。甲磺酸伊马替尼以剂量依赖性方式有效减少 SSc 和正常真皮成纤维细胞中 COL1A1、COL1A2 和纤连蛋白 1 信使 RNA 的基础合成。 TGFβ和PDGF刺激后ECM蛋白的诱导也受到甲磺酸伊马替尼的剂量依赖性强烈抑制。这些结果在蛋白质水平上得到了证实。甲磺酸伊马替尼不会改变真皮成纤维细胞的增殖或诱导细胞凋亡和坏死。与体外研究结果一致，甲磺酸伊马替尼减少了实验性真皮纤维化中的真皮厚度、肌成纤维细胞数量和ECM蛋白的合成，且没有毒副作用的证据。结论。这些数据表明，生物学相关浓度的甲磺酸伊马替尼在体外和体内具有有效的抗纤维化作用，且无毒副作用。考虑到其良好的药代动力学和用于其他疾病的临床经验，甲磺酸伊马替尼是治疗 SSc 等纤维化疾病的有前途的候选药物。
Objective. Imatinib mesylate is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor 13 (TGF beta) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).Methods. The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin-induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.Results. Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF beta and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects.Conclusion. These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.