Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy.
Eur J Pharmacol. 2013 Sep 5;715(1-3):296-303. doi: 10.1016/j.ejphar.2013.05.007. Epub 2013 May 23.
Inflammation plays a crucial role in muscle remodeling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice, a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most of the remaining macrophages displayed characteristics of the transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing during chronic muscle damage. This, alongside its already approved use in human, makes molsidomine a drug with a significant therapeutic potential in muscular dystrophies.
在急性和慢性损伤后肌肉重塑和修复中，炎症起着至关重要的作用，特别是在肌肉营养不良症中，这是一组导致肌肉退化的异质性遗传疾病。一氧化氮（NO）生成缺陷是肌肉营养不良症的一个关键致病事件，因此，NO 供体已被探索用于这种疾病的新疗法。我们研究了其中一种药物——莫索尼定的免疫调节作用，它能够减缓α-横纹肌聚糖缺失小鼠（一种肢带型肌肉营养不良症 2D 的模型）的肌肉营养不良症的进展，该模型与其他肌肉营养不良症具有许多肌肉退化的共同特征。用莫索尼定治疗α-横纹肌聚糖缺失小鼠，并在选定的时间点评估药物对炎症浸润和肌肉修复的影响。我们发现，莫索尼定治疗能有效地调节营养不良肌肉内炎症浸润的特征，增强其愈合功能。最初，莫索尼定增强了巨噬细胞的募集，促进了细胞碎片的更有效清除和有效的组织再生。在后期，莫索尼定显著减少了炎症浸润的程度，其持续存在会加剧肌肉损伤：大部分残留的巨噬细胞表现出过渡群体的特征，与纤维化减少和肌肉组织保存增加有关。莫索尼定的双重作用，即已知的 NO 供体和我们现在确定的免疫调节功能，表明它在慢性肌肉损伤期间的组织愈合中具有独特的潜力。这一点，加上它在人类中的已批准用途，使莫索尼定成为肌肉营养不良症中具有显著治疗潜力的药物。
