髓鞘碎片在大鼠弥漫性轴索损伤中的作用和相关机制研究

Diffuse axonal injury (DAI) is a kind of severe traumatic brain injuries, which would lead to the worst outcome among head trauma. Up to now, the mechanism of DAI is still unknown, and as a result there is still no specific method on the treatment of DAI. Myelin debris is an important injurious agnent as for kinds of diseases in central nervous system, and it mainly works through inflammatory reaction. We found that several inflammatory factors related to myelin debris would be expressed increasingly dramatically after DAI; moreover, the myelin debris would be existed constantly at the site of axonal injury, even the amount would be increased on the sub-acute stage of DAI comparing to that on the acute stage. In further, we speculate that myelin debris would lead to inflammatory reaction on the early stage of DAI, and the inflammatory reaction is able to produce more myelin debris which would aggravate the reaction; As a result, the inflammatory reaction would be aggravated and delayed, and lead to more serious axonal injury for the secondary axonal injury. So we plan to validate the hypothesis that myelin debris participates in secondary axonal injury after DAI by inflammatory reaction through animal expriment; in further, we would observe the outcome of DAI afther intensifying the elimination of myelin debris, which aims at searching for the treatment of DAI based on myelin debris.

弥漫性轴索损伤（DAI）是颅脑创伤中预后最差且发病率极高的一种类型，迄今为止由于未明确其损伤机制，临床上仍缺少有效的治疗手段。髓鞘碎片是多种神经系统损伤性疾病的重要媒介，其主要机制为炎症反应，但髓鞘碎片在DAI中作用的研究尚未见报导。我们在前期的研究中发现TNF-α等与髓鞘碎片密切相关的炎症因子在大鼠DAI后表达水平显著上调；同时，DAI后轴索损伤部位的髓鞘碎片将持续存在，亚急性期甚至较急性期有所增加。结合已有的文献，我们推测：在DAI中，髓鞘碎片能够诱导早期的炎症反应，而炎症反应又导致更多的髓鞘碎片产生并加重炎症反应，从而引起炎症反应长期化，最终造成轴索的继发性损伤。本项目拟通过动物实验研究，证实髓鞘碎片在DAI中通过炎症反应参与了轴索的继发性损伤过程，并进一步通过观察大鼠DAI模型中促进髓鞘清除后，炎症反应的强度和轴索损伤的转归，探索以髓鞘碎片为靶点的DAI治疗方案的可行性。

弥漫性轴索损伤（DAI）是颅脑创伤中预后最差且发病率极高的一种类型，迄今为止由于未明确其损伤机制，临床上仍缺少有效的治疗手段。髓鞘碎片是多种神经系统损伤性疾病的重要媒介，其主要机制为炎症反应，但髓鞘碎片在DAI中作用的研究尚未见报导。结合已有的文献，我们推测：在DAI中，髓鞘碎片能够诱导早期的炎症反应，而炎症反应又导致更多的髓鞘碎片产生并加重炎症反应，从而引起炎症反应长期化，最终造成轴索的继发性损伤。在该项目的执行过程中，我们成功建立的大鼠DAI模型，并发现在损伤位点TNF-α、IL-1β和IL-6炎症因子的表达量在伤后30min即显著升高，并在伤后12-24小时达到高峰，之后缓慢下降，至伤后7天恢复正常水平。在伤后1天、7天、14天和28天通过油红O（OR）染色法检测实验组与空白对照组新皮层、海马齿状回、脑干区域髓鞘碎片的数量，并比较各时间点的变化。结果发现对照组内在皮层、海马及脑干内均未见明显RO染色阳性颗粒。实验组中，伤后1天，以上区域脑组织内仍未见明显阳性颗粒。在皮层组织内，伤后7天髓鞘碎片可观察到较多的髓鞘碎片分布，伤后14天到达高峰，至28天时，阳性颗粒数目降至与7天时数目基本相当；在海马组织内，伤后7天髓鞘碎片可观察到较多的髓鞘碎片分布，伤后14天到达高峰，至28天时可观察到的髓鞘碎片基本消失；在脑干组织内，伤后7天髓鞘碎片可观察到较多的髓鞘碎片分布，至伤后14天、28天髓鞘碎片数量明显下降。该研究的结论提示大鼠弥漫性轴索损伤后，髓鞘碎片可在中枢神经系统内长期存在。作为重要的炎症介质，髓鞘碎片的长期存在将造成中枢神经系统内的炎症反应并进一步加重轴索损伤。