Grounds Miranda D, Torrisi Jo
School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Hwy., Crawley, Western Australia, Australia 6009.
FASEB J. 2004 Apr;18(6):676-82. doi: 10.1096/fj.03-1024com.
Necrosis of skeletal muscle fibers in the lethal childhood myopathy Duchenne muscular dystrophy (DMD) results from defects in the cell membrane-associated protein, dystrophin. This study tests the novel hypothesis that the initial sarcolemmal breakdown resulting from dystrophin deficiency is exacerbated by inflammatory cells and that cytokines, specifically tumor necrosis factor-alpha (TNFalpha), contribute to muscle necrosis. To block in vivo TNFalpha bioactivity, young dystrophic mdx mice (a model for DMD) were injected weekly from 7 days of age with the anti-TNFalpha antibody Remicade before the onset of muscle necrosis and dystropathology that normally occurs at 21 days postnatally. The extent of inflammation, muscle necrosis, and myotube formation was measured by histological analysis from 18 to 28 days and muscle damage was also visualized by penetration of Evans blue dye into myofibers. Data from Remicade-treated and control mdx mice were compared with mdx/TNFalpha-/- mice that lack TNFalpha. Pharmacological blockade of TNFalpha activity with Remicade clearly delayed and greatly reduced the breakdown of dystrophic muscle, in marked contrast to the situation in mdx and mdx/TNFalpha-/- mice. Remicade had no adverse effect on new muscle formation. Remicade is a highly specific anti-inflammatory intervention, and clinical application to muscular dystrophies is suggested by this marked protective effect against skeletal muscle breakdown.
在致死性儿童肌病杜氏肌营养不良症（DMD）中，骨骼肌纤维坏死是由细胞膜相关蛋白——抗肌萎缩蛋白的缺陷所致。本研究检验了一个新假说，即抗肌萎缩蛋白缺乏导致的初始肌膜破裂会因炎症细胞而加剧，且细胞因子，特别是肿瘤坏死因子-α（TNFα），会促使肌肉坏死。为了在体内阻断TNFα的生物活性，在出生后21天通常会出现的肌肉坏死和肌病病理改变发生之前，从7日龄开始每周给年幼的营养不良性mdx小鼠（DMD模型）注射抗TNFα抗体类克。在18至28天通过组织学分析测量炎症程度、肌肉坏死情况和肌管形成情况，还通过伊文思蓝染料渗入肌纤维来观察肌肉损伤情况。将类克治疗的mdx小鼠和对照mdx小鼠的数据与缺乏TNFα的mdx/TNFα-/-小鼠的数据进行比较。用类克对TNFα活性进行药理阻断明显延迟并大大减少了营养不良性肌肉的分解，这与mdx和mdx/TNFα-/-小鼠的情况形成显著对比。类克对新肌肉形成没有不良影响。类克是一种高度特异性的抗炎干预措施，这种对骨骼肌分解的显著保护作用提示了其在肌营养不良症临床应用中的可能性。
