Imatinib attenuates skeletal muscle dystrophy in mdx mice
Imatinib attenuates skeletal muscle dystrophy in mdx mice
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DOI：
10.1096/fj.09-129833
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发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Zhou, Lan
中科院分区：
文献类型：
--
作者：
Huang, Ping;Zhao, Xinyu S.;Zhou, Lan
Duchenne-Meryon肌营养不良症（DMD）是最常见和最致命的遗传性肌肉疾病。改善肌肉坏死、炎症和纤维化是DMD的重要治疗方法。伊马替尼是一种抗纤维化药物，在各种动物模型的肝、肾、肺和皮肤中显示出抗纤维化和抗纤维化作用。本研究测试了伊马替尼在mdx小鼠（DMD小鼠模型）中的抗纤维化和抗纤维化作用。我们在mdx小鼠四肢肌肉炎症高峰期和膈肌纤维化开始时腹腔注射伊马替尼。对照接受PBS媒介物或不进行处理。通过测量血清CK活性、肌内膜CD 45免疫反应性炎症面积、肌内膜III型胶原沉积和后肢握力来评价肌肉坏死、炎症、纤维化和功能。在膈肌组织和腹膜巨噬细胞和骨骼肌成纤维细胞的原代培养物中，通过蛋白质印迹法评估伊马替尼酪氨酸激酶靶点的磷酸化。伊马替尼显著减少mdx小鼠的肌肉坏死、炎症和纤维化，并显著改善后肢握力。临床疾病的减少伴随着c-abl和PDGFR磷酸化的抑制以及TNF-α和IL-1 β表达的抑制。伊马替尼治疗DMD可以通过抑制c-abl和PDGFR信号通路以及下游炎性细胞因子和纤维化基因表达来改善肌肉坏死，炎症和纤维化。黄，P.，Zhao，X.美国，菲尔兹，M.，兰索霍夫河M.，周湖，加-地伊马替尼减轻mdx小鼠骨骼肌营养不良。FASEB J. 23，2539-2548（2009）
Duchenne-Meryon muscular dystrophy (DMD) is the most common and lethal genetic muscle disease. Ameliorating muscle necrosis, inflammation, and fibrosis represents an important therapeutic approach for DMD. Imatinib, an antineoplastic agent, demonstrated antiinflammatory and antifibrotic effects in liver, kidney, lung, and skin of various animal models. This study tested antiinflammatory and antifibrotic effects of imatinib in mdx mice, a DMD mouse model. We treated mdx mice with intraperitoneal injections of imatinib at the peak of limb muscle inflammation and the onset of diaphragm fibrosis. Controls received PBS vehicle or were left untreated. Muscle necrosis, inflammation, fibrosis, and function were evaluated by measuring serum CK activity, endomysial CD45 immunoreactive inflammation area, endomysial collagen III deposition, and hind limb grip strength. Phosphorylation of the tyrosine kinase targets of imatinib was assessed by Western blot in diaphragm tissue and in primary cultures of peritoneal macrophages and skeletal muscle fibroblasts. Imatinib markedly reduced muscle necrosis, inflammation, and fibrosis, and significantly improved hind limb grip strength in mdx mice. Reduced clinical disease was accompanied by inhibition of c-abl and PDGFR phosphorylation and suppression of TNF-alpha and IL-1 beta expression. Imatinib therapy for DMD may hold promise for ameliorating muscle necrosis, inflammation, and fibrosis by inhibiting c-abl and PDGFR signaling pathways and downstream inflammatory cytokine and fibrotic gene expression.-Huang, P., Zhao, X. S., Fields, M., Ransohoff, R. M., Zhou, L. Imatinib attenuates skeletal muscle dystrophy in mdx mice. FASEB J. 23, 2539-2548 (2009)