间充质干细胞移植治疗脓毒症的机制研究

Sepsis can lead to septic shock and multiple organ failure, which has a high mortality rate due to the lack of effective treatment. The studies found that in sepsis oxidative stress and redox imbalance caused by the relevant materials. In the target organs of infected, significant down-regulation of Keap1/Nrf2/ARE signaling pathway may be an important factor resulting in oxidative stress and sepsis worsened. Mesenchymal stem cells (MSCs) can secrete superoxide dismutase (3 SOD3) for anti-oxidative stress effect. We found that MSCs transplantation can inhibit inflammatory reaction of important organs and improve the survival rate of septic mice. Therefore, we put forward a hypothesis: MSCs transplantation was significantly up-regulated in important target organ oxidative stress and inhibited the inflammation caused by sepsis, clinical symptom and improved the septic death rate via the expression and activity of Keap1/Nrf2/ARE signaling molecules in the secretion of SOD3. We will adopted different culture conditions of MSCs to transplant on septic mice, including application of cell biology, molecular biology and molecular imaging method, combined with in vivo and in vitro experiments to validate our proposed scientific hypotheses, which will provide a new direction and theoretical basis for MSCs in the therapy of sepsis.

脓毒症可导致脓毒性休克、多器官功能衰竭，由于缺乏有效的治疗手段，病死率极高。研究发现脓毒症与氧化-还原物质失衡所致的氧化应激有关，其中，在被感染的靶器官中，Nrf2/Keap1/ARE信号通路的显著下调可能是导致氧化应激、脓毒症恶化的重要因素；间充质干细胞（MSCs）可分泌超氧化物歧化酶3（SOD3）而发挥抗氧化应激作用。我们发现：MSCs移植能抑制重要脏器的炎症反应、显著提高脓毒症小鼠的生存率。因此，我们提出假设：移植MSCs可通过其分泌的SOD3显著上调重要靶器官的Nrf2/Keap1/ARE信号分子的表达及活性，抑制脓毒症导致的氧化应激及炎症反应，从而可显著改善脓毒症的临床症状及降低死亡率。我们将应用不同条件下培养的MSCs，对脓毒症小鼠进行细胞移植，应用细胞生物学、分子生物学和分子影像学等手段，结合体内外实验来验证我们提出的科学假设，这将为MSCs治疗脓毒症提供新的方向和理论依据。

脓毒症发生时，机体会发生一系列变化，包括氧化应激、炎症反应，氧化应激可引起炎症反应，同时，炎症反应也可以引起氧化应激，抑制脓毒症导致的氧化应激及炎症反应，可显著改善脓毒症的临床症状及降低死亡率。间充质基质细胞（MSCs）的移植是治疗脓毒症的一种有前途的策略。MSCs移植能抑制重要脏器的炎症反应，显著提高脓毒症小鼠的生存率。天然杀伤细胞（NK）在脓毒症的发展中很重要，其功能可以被MSCs抑制。本研究通过细胞共培养，小干扰RNA转染，酶联免疫吸附测定，荧光测定，蛋白质印迹和病理学检查等方法，探究了MSCs抑制了脓毒症时NK细胞功能和增殖的机制可能涉及增加了IL-10水平并抑制Janus激酶/信号转导子中的细胞因子信号传导3（SOCS3）以及其他途径的组成转录途径，这将为MSCs治疗脓毒症提供新的方向和理论依据。