Excessive collagen accumulation in dystrophic (mdx) respiratory musculature is independent of enhanced activation of the NF-kappaB pathway.
Excessive collagen accumulation in dystrophic (mdx) respiratory musculature is independent of enhanced activation of the NF-kappaB pathway.
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DOI：
10.1016/j.jns.2010.04.007
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发表时间：
2010-07-15
影响因子：
4.4
通讯作者：
Carlson, C. G.
中科院分区：
文献类型：
--
作者：
Graham, K. M.;Singh, R.;Millman, G.;Malnassy, G.;Gatti, F.;Bruemmer, K.;Stefanski, C.;Curtis, H.;Sesti, J.;Carlson, C. G.
关键词：
骨骼肌纤维化存在于mdx小鼠（Duchenne营养不良的模型）的膈肌中。在小鼠和人类中，营养不良的肌肉表现出NF-κB信号传导的显著增加。该途径的各种抑制剂，如吡咯烷二硫代氨基甲酸酯（PDTC）和熊去氧胆酸（UDCA），已被证明对营养不良（mdx）肌肉具有有益作用。本研究描述了mdx肌肉组织中纤维化的发展，并确定了PDTC和UDCA的纤维溶解疗效。结果表明，在非营养不良小鼠和mdx小鼠中，胶原积累以及纤维形成（TGF-β1）和纤维溶解（MMP-9）介质的表达依赖于肌肉来源。在实质性肌肉变性和细胞浸润之前，在mdx呼吸肌组织中观察到过度胶原积聚，并且与TGF-β1表达的营养不良性增加相关，而MMP-9表达没有相应的增加。PDTC或UDCA处理不影响mdx呼吸肌组织中的胶原沉积或TGF-β1表达。这些结果表明，胶原蛋白的营养不良性增加是NF-κ B非依赖性信号传导异常的结果，并且减少过度胶原蛋白积聚的努力将需要更特异性地减少TGF-β1信号传导或增强基质金属蛋白酶的表达和/或活性的治疗。
Skeletal muscle fibrosis is present in the diaphragm of the mdx mouse, a model for Duchenne dystrophy. In both the mouse and human, dystrophic muscle exhibits pronounced increases in NF-κB signaling. Various inhibitors of this pathway, such as pyrrolidine dithiocarbamate (PDTC) and ursodeoxycholic acid (UDCA), have been shown to have beneficial effects on dystrophic (mdx) muscle. The present study characterizes the development of fibrosis in the mdx musculature, and determines the fibrolytic efficacy of PDTC and UDCA. The results indicate that collagen accumulation and the expression of fibrogenic (TGF-β1) and fibrolytic (MMP-9) mediators is dependent on muscle origin in both nondystrophic and mdx mice. Excessive collagen accumulation is observed in the mdx respiratory musculature prior to substantial muscle degeneration and cellular infiltration, and is associated with dystrophic increases in the expression of TGF-β1 with no corresponding increases in MMP-9 expression. Treatment with PDTC or UDCA did not influence collagen deposition or TGF-β1 expression in the mdx respiratory musculature. These results indicate that dystrophic increases in collagen are the result of NF-κB–independent signaling abnormalities, and that efforts to reduce excessive collagen accumulation will require treatments to more specifically reduce TGF-β1 signaling or enhance the expression and/or activity of matrix metalloproteases.
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