骨骼肌损伤修复过程中巨噬细胞的作用及IGF-1/MGF干预效果与机制研究

。.Repair of skeletal muscle injury has always been concerned in the field of sports medicine world widely. An important recent addition to this hot topic is that not only the satellite cells but the immune cells especially the macrophages may also play the important role during the repair process. However, the exact role and the regulation of macrophage in the repair are still not clear. Currently, the clinical treatment of severe skeletal injury is also limited and poorly developed by the absence of effective local pharmacologic intervention. .In this project, we establish an animal model of skeletal injury, combined with an in vivo model of macrophage elimination, to investigate the role and the effects of macrophage and macrophage related factors during the repair process after skeletal muscle injury. Exogenous IGF-1 and MGF are also administrated locally to explore their effects and possible mechanisms in the intervention of the repair process. Moreover, the effects of IGF-1 and MGF on macrophage function are systemically studied by the in vitro model to further investigate the roles of IGF-1 and MGF in the repair of skeletal muscle injury from the view of macrophage. .Our research project is expected to reveal the role and the possible regulation mechanism of macrophage in the repair of skeletal muscle injury, and develop the potential pharmacologic treatment of severe skeletal muscle injury for clinical research and practice.

骨骼肌损伤的修复一直是国际运动医学界研究的热点。近年来，有关对骨骼肌损伤修复机理的研究已不仅局限于肌卫星细胞本身，免疫细胞特别是巨噬细胞在肌卫星细胞活化及损伤修复中的重要性正逐步被认识，但其作用及作用机制目前仍处于初步探索阶段。骨骼肌严重损伤的临床治疗手段至今仍较为局限，尤其是缺乏科学有效的外源性药物进行局部干预以促进修复。因此，本研究通过构建骨骼肌钝挫伤动物模型，并借助在体巨噬细胞剔除技术，跟踪研究骨骼肌损伤修复过程中巨噬细胞以及相关的活性因子的变化、作用规律和调控机制；局部应用IGF-1和MGF这两种生长因子，对骨骼肌损伤后的修复进行干预，并观察其对损伤后修复进程的影响；离体状态下研究IGF-1和MGF对巨噬细胞功能的影响，以揭示巨噬细胞在骨骼肌损伤修复中的关键作用及其机制，并从巨噬细胞角度深刻揭示IGF-1和MGF参与骨骼肌损伤修复的可能机制，为进一步的临床研究及应用提供理论依据。

骨骼肌损伤的修复一直是国际运动医学界研究的热点。近年来，有关对骨骼肌损伤修复机理的研究已不仅局限于肌卫星细胞本身，免疫细胞特别是巨噬细胞在肌卫星细胞活化及损伤修复中的重要性正逐步被认识，但其作用及作用机制目前仍处于初步探索阶段。骨骼肌严重损伤的临床治疗手段至今仍较为局限，尤其是缺乏科学有效的外源性药物进行局部干预以促进修复。因此，本研究通过构建骨骼肌钝挫伤动物模型，并借助在体巨噬细胞剔除技术，跟踪研究了骨骼肌损伤修复过程中巨噬细胞以及相关的活性因子的变化、作用规律和调控机制。结果表明，骨骼肌损伤后，多种肌再生因子表达上调，它们可能在损伤骨骼肌再生过程中发挥重要作用。剔除巨噬细胞，可加剧骨骼肌再生后期阶段炎症和氧化应激水平，下调IGF-1和MGF等肌再生因子表达水平，加剧骨骼肌纤维化修复，使再生肌纤维横截面积缩小，损害骨骼肌再生，表明巨噬细胞在骨骼肌再生中具有不可或缺的重要作用。此外，我们还用IGF-1和MGF这两种生长因子局部注射对骨骼肌损伤后的修复进行了观察，研究了其对损伤后修复进程的影响。结果发现，这两种再生因子局部注射，可显著提高Arg1、Ang1、 FGF6、LIF、M-CSF、IL-12等因子表达水平，有助于损伤骨骼肌形态学修复。最后，我们还在离体状态下研究IGF-1和MGF对巨噬细胞功能的影响，以揭示巨噬细胞在骨骼肌损伤修复中的关键作用及其机制。结果表明，巨噬细胞具有向IGF-1或MGF趋化性，IGF-1和MGF还可调控骨骼肌卫星细胞增殖和分化能力。以上结果提示巨噬细胞来源的IGF-1和MGF可能在骨骼肌再生中发挥重要作用，IGF-1和MGF外源性用药可作为治疗骨骼肌损伤的手段之一。这些结果将为临床应用这些因子治疗骨骼肌损伤提供实验依据。