脐带MSCs调控严重烧伤过度炎症反应及其机制的研究

Following major burn injuries,the inflammatory cells including macrophaes will be activated and release a large number of inflammatory mediators, which results in an extensive inflammatory reaction and may lead to shock, organ dysfunction or even death. It has been demonstrated that umbilical cord MSCs are able to attenuate the inflammatory reaction of systemic lupus erythematosus, ulcerative colitis, hepatic fibrosis and other diseases. Our pilot study also showed that umbilical cord MSCs can attenuate the infiltration of inflammatory cells into the wounds of sever burned rats. The aims of this study are: 1.to further investigate the inhibitory effects of umbilical cord MSCs on inflammatory reaction; 2. to confirm the role of TSG-6/PGE2 on the inhibitory effects of umbilical cord MSCs; 3. to explore the effects of TSG-6/PGE2 on MAPK/NF-kB pathway, production of pro-inflammatory mediators, alteration of immunophenotype, and the infiltration of macrophages in vitro. Through this study, we hope to expand our knowledge on the inhibitory mechanism of umbilical cord MSCs on inflammation, and to provide new target in treating sever burned patients.

严重烧伤后，巨噬细胞等炎症启动细胞被激活，释放大量炎症介质，引起机体过度炎症反应，进而导致休克、脏器损害，甚至危及患者生命。研究已证实，脐带间充质干细胞(MSCs)能够显著改善系统性红斑狼疮、溃疡性结肠炎及肝纤维化等疾病的炎症反应。我们预实验也证实，脐带MSCs 不仅可以减轻严重烧伤大鼠创面炎性细胞的浸润，而且可以显著降低全身炎症介质水平。本项目拟在预实验的基础上，进一步研究脐带MSCs的抗炎效果，明确MSCs旁分泌的TSG-6/PGE2抗炎蛋白在其发挥抗炎作用中的地位。MAPK/NF-kB信号是介导严重烧伤过度炎症反应的主要信号通路，本实验拟建立严重烧伤过度炎症反应体外模型，深入探讨TSG-6/PGE2对巨噬细胞MAPK/NF-kB信号的调控情况以及其对巨噬细胞合成促炎因子、免疫表型改变以及迁移浸润等的影响。从而丰富脐带MSCs抗炎机制的研究，并为临床治疗严重烧伤患者提供新思路。

严重烧伤可诱导机体发生过度炎症反应，随之加重休克、脏器损害，甚至危及患者生命。本课题首先根据过度炎症反应的最新诊断标准，通过严格的对比分析30%和50% TBSA深度烧伤大鼠的各项指标，分析得出50% TBSA大鼠可建立严重烧伤早期过度炎症反应的稳定动物模型。进一步研究是将人脐带间充质干细胞移植入严重烧伤过度炎症反应大鼠体内，结果显示，人脐带间充质干细胞是通过旁分泌重要的抗炎蛋白-肿瘤坏死因子刺激因子/蛋白6（TSG-6），显著下调了促炎的P38和JNK信号，进而发挥抗严重烧伤过度炎症反应的作用（具体的研究结果见结题报告）。此外，课题组有关人脐带间充质干细胞的抗炎机制，进行了深入的探讨，比如研究发现其还可以通过旁分泌的外泌体exosomes，介导miR-181c下调TRL4/NF-kB促炎信号，进而发挥治疗严重烧伤过度严重反应的作用。这些综合的数据丰富了hUCMSCs的抗炎机制，并为临床治疗严重烧伤患者提供新思路。