Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor β in the skin of mice with scleroderma-like features and prevents the development of the disease
Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor β in the skin of mice with scleroderma-like features and prevents the development of the disease
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DOI：
10.1002/art.34354
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发表时间：
2012-06-01
影响因子：
--
通讯作者：
Batteux, Frederic
中科院分区：
文献类型：
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作者：
Kavian, Niloufar;Servettaz, Amelie;Batteux, Frederic
目的 系统性硬化症（SSc）的特点是皮肤和内脏器官纤维化、血管功能障碍和免疫失调。血小板源性生长因子（PDGF）与纤维化的发展和血管功能失调有关。我们研究了舒尼替尼和索拉非尼这两种干扰 PDGF 信号传导的酪氨酸激酶抑制剂在弥漫性 SSc 小鼠模型中的作用。方法 通过每天皮下注射 HOCl 诱导 BALB/c 小鼠 SSc，持续 6 周。小鼠被随机分配接受舒尼替尼、索拉非尼或载体治疗。通过蛋白质印迹和免疫组织化学分析评估皮肤中天然和磷酸化 PDGF 受体 β (PDGFR β) 和血管内皮生长因子受体 (VEGFR) 的水平。通过组织学和生化方法评估皮肤和肺纤维化。通过酶联免疫吸附测定检测自身抗体，并通过流式细胞术分析脾细胞群。结果注射 HOCl 的 SSc 小鼠纤维化皮肤中 PDGFR β 和 VEGFR 的磷酸化程度高于注射 PBS 的小鼠。注射次氯酸可诱导 BALB/c 小鼠皮肤和肺纤维化，增加纤维化皮肤区域成纤维细胞的增殖率，增加脾 B 细胞和 T 细胞计数，并增加 BALB/c 小鼠的抗 DNA 拓扑异构酶 I 自身抗体水平。舒尼替尼可降低所有这些特征，但索拉非尼则不会。舒尼替尼显着降低 PDGF 和 VEGF 受体的磷酸化。结论 舒尼替尼抑制过度活化的 PDGF 和 VEGF 通路可阻止 HOCl 诱导的小鼠 SSc 纤维化的发展，并可能代表一种新的 SSc 治疗方法，用于临床试验。
Objective Systemic sclerosis (SSc) is characterized by fibrosis of the skin and visceral organs, vascular dysfunction, and immunologic dysregulation. Platelet-derived growth factors (PDGFs) have been implicated in the development of fibrosis and dysregulation of vascular function. We investigated the effects of sunitinib and sorafenib, two tyrosine kinase inhibitors that interfere with PDGF signaling, in a mouse model of diffuse SSc. Methods SSc was induced in BALB/c mice by subcutaneous injections of HOCl daily for 6 weeks. Mice were randomized to treatment with sunitinib, sorafenib, or vehicle. The levels of native and phosphorylated PDGF receptor beta (PDGFR beta) and vascular endothelial growth factor receptor (VEGFR) in the skin were assessed by Western blot and immunohistochemical analyses. Skin and lung fibrosis were evaluated by histologic and biochemical methods. Autoantibodies were detected by enzyme-linked immunosorbent assay, and spleen cell populations were analyzed by flow cytometry. Results Phosphorylation of PDGFR beta and VEGFR was higher in fibrotic skin from HOCl-injected mice with SSc than from PBS-injected mice. Injections of HOCl induced cutaneous and lung fibrosis, increased the proliferation rate of fibroblasts in areas of fibrotic skin, increased splenic B cell and T cell counts, and increased antiDNA topoisomerase I autoantibody levels in BALB/c mice. All of these features were reduced by sunitinib but not by sorafenib. Sunitinib significantly reduced the phosphorylation of both PDGF and VEGF receptors. Conclusion Inhibition of the hyperactivated PDGF and VEGF pathways by sunitinib prevented the development of fibrosis in HOCl-induced murine SSc and may represent a new SSc treatment for testing in clinical trials.