Sacramento Chester Bittencourt, Cantagalli Vanessa Dionisio, Grings Mariana, Carvalho Leonardo Pinto, Baptista-Silva José Carlos Costa, Beutel Abram, Bergamaschi Cassia Toledo, de Campos Junior Ruy Ribeiro, de Moraes Jane Zveiter, Takiya Christina Maeda, Samoto Vívian Yochiko, Borojevic Radovan, da Silva Flavia Helena, Nardi Nance Beyer, Dohmann Hans Fernando, Junior Hamilton Silva, Valero Valderez Bastos, Han Sang Won
Interdisciplinary Center for Gene Therapy, Federal University of São Paulo, São Paulo, Brazil.
J Gene Med. 2009 Apr;11(4):345-53. doi: 10.1002/jgm.1298.
Granulocyte-colony-stimulating factor (GM-CSF) is a pleiotropic factor for hematopoiesis that stimulates myeloblasts, monoblasts and mobilization of bone marrow stem cells. Therefore, the GM-CSF gene is a potential candidate for vessel formation and tissue remodeling in the treatment of ischemic diseases.
A new mouse limb ischemia was established by surgery and gene transfer was performed by injection of 100 microg of a plasmid carrying GM-CSF. Muscle force and weight, histology, capillary density, circulating stem cells and monocytes were determined after 3-4 weeks.
More than 60% of nontreated ischemic animals showed gangrene below the heel after 4 weeks, whereas the GM-CSF gene-treated animals showed only darkening of nails or toes. These animals demonstrated a full recovery of the affected muscles in terms of weight, force and muscle fiber structure, but the muscles of nontreated ischemic animals lost approximately 50% weight, 86% force and their regular structure. When the GM-CSF gene was injected into the contralateral limb, only partial loss was observed, demonstrating a distant effect of GM-CSF. The capillary density in the GM-CSF-treated group was 52% higher in relation to the nontreated group. Blood analysis by flow cytometry showed that the GM-CSF-treated group had 10-20% higher levels of circulating monocytes and Sca-1(+).
We conclude that the direct administration of GM-CSF gene in limb ischemia had a strong therapeutic effect because it promoted the recovery of muscle mass, force and structure by mobilizing therapeutic cells and augmenting the number of vessels.
粒细胞集落刺激因子（GM-CSF）是一种对造血具有多效性的因子，可刺激成髓细胞、单核母细胞并促进骨髓干细胞的动员。因此，GM-CSF基因是治疗缺血性疾病时血管形成和组织重塑的潜在候选基因。
通过手术建立新的小鼠肢体缺血模型，并通过注射100微克携带GM-CSF的质粒进行基因转移。3-4周后测定肌肉力量和重量、组织学、毛细血管密度、循环干细胞和单核细胞。
超过60%未经治疗的缺血动物在4周后足跟以下出现坏疽，而经GM-CSF基因治疗的动物仅表现为指甲或脚趾变黑。这些动物在重量、力量和肌纤维结构方面受影响的肌肉完全恢复，而未经治疗的缺血动物的肌肉重量减轻约50%，力量下降86%，且失去正常结构。当将GM-CSF基因注入对侧肢体时，仅观察到部分损失，表明GM-CSF具有远程效应。GM-CSF治疗组的毛细血管密度比未治疗组高52%。流式细胞术血液分析显示，GM-CSF治疗组循环单核细胞和Sca-1(+)水平高10-20%。
我们得出结论，在肢体缺血中直接给予GM-CSF基因具有强大的治疗效果，因为它通过动员治疗性细胞和增加血管数量促进了肌肉质量、力量和结构的恢复。
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