Immunomodulation of TGF-beta1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: Implications for antifibrotic therapy
Immunomodulation of TGF-beta1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: Implications for antifibrotic therapy
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DOI：
10.1016/j.jneuroim.2006.03.005
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发表时间：
2006-06-01
影响因子：
3.3
通讯作者：
Confalonieri, Paolo
中科院分区：
文献类型：
--
作者：
Andreetta, Francesca;Bernasconi, Pia;Confalonieri, Paolo
肌肉中不可逆的结缔组织增生是杜氏肌营养不良症（DMD）的病理标志，杜氏肌营养不良症是由于缺乏肌膜蛋白肌营养不良蛋白而引起的遗传性退行性肌肉疾病。转化生长因子β 1（TGF-β 1）的局灶性释放参与纤维化发展。鼠肌营养不良症（mdx）是遗传同源的DMD和组织病理学变化的DMD肌肉中发生的老年mdx小鼠的隔膜。为了研究纤维化的早期发展和TGF-β 1的参与，我们评估了6-36周龄mdx和C57/BL 6（对照）小鼠的横膈膜纤维化，并使用实时PCR和ELISA来确定TGF-β 1的表达。从第6周开始，mdx中发现纤维化和TGF+ β 1表达显著增加。用针对TGF+ β 1的中和抗体处理的小鼠具有较低水平的TGF+ β 1蛋白、减少的纤维化、不变的肌肉纤维变性/再生，但增加的炎性细胞（CD 4+淋巴细胞）。这些数据表明mdx隔膜中的早期和进行性纤维化伴随TGF-β 1上调。减少TGF-β 1似乎是一种有希望的肌肉纤维化的治疗方法，但需要进一步的研究来评估TGF-β 1免疫调节对免疫系统的长期影响。(c)2006 Elsevier B. V.保留所有权利。
Irreversible connective tissue proliferation in muscle is a pathological hallmark of Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease due to lack of the sarcolemmal protein dystrophin. Focal release of transforming growth factor-betal (TGF-beta 1) is involved in fibrosis development. Murine muscular dystrophy (mdx) is genetically homologous to DMD and histopathological alterations comparable to those in DMD muscles occur in diaphragm of older mdx mice. To investigate the early development of fibrosis and TGF-beta 1 involvement, we assessed diaphragms in 6-36-week-old mdx and C57/BL6 (control) mice for fibrosis, and used real-time PCR and ELISA to determine TGF-1 expression. Significantly greater fibrosis and TGF+beta 1 expression were found in mdx from the 6th week. Mice treated with neutralizing antibody against TGF+beta 1 had lower levels of TGF+beta 1 protein, reduced fibrosis, unchanged muscles fiber degeneration/ regeneration, but increased inflammatory cells (CD4+ lymphocytes). These data demonstrate early and progressive fibrosis in mdx diaphragm accompanied by TGF-beta 1 upregulation. Reduction of TGF-beta 1 appears promising as a therapeutic approach to muscle fibrosis, but further studies are required to evaluate long term effects of TGF-beta 1 immunomodulation on the immune system. (c) 2006 Elsevier B.V. All rights reserved.