MSC调控ARDS炎症反应的新机制——旁分泌TGF-β诱导Treg/Th17极化平衡

抑炎和促炎反应失衡所致的炎症反应失控是ARDS发生发展的关键。MSC能有效控制ARDS失控的炎症反应，然而其具体作用环节和机制尚不清楚。Treg/Th17极化失衡在ARDS炎症反应失控中扮演着重要角色。MSC能调节Treg和Th17极化且能分泌二者极化的主要调节因子TGF-β。结合我们预实验发现MSC能上调ARDS小鼠肺组织中TGF-β水平和Treg/Th17计数比，推测旁分泌TGF-β诱导Treg/Th17极化平衡可能是MSC纠正ARDS炎症反应失衡的机制。本研究拟在MSC与Naïve CD4+T间接共培养和LPS诱导ARDS小鼠模型之上，利用基因工程上调或抑制MSC对TGF-β的分泌，体外以及在体实验证实ARDS时MSC通过旁分泌TGF-β能促进Naïve CD4+T向Treg极化而抑制其向Th17极化，诱导Treg/Th17极化平衡，从而纠正失控的炎症反应、减轻肺损伤并促进肺修复。

Acute respiratory distress syndrome (ARDS) is characterized by uncontrolled inflammation caused by the imbalance of anti-inflammation and pro-inflammation. Bone marrow derived Mesenchymal stem cells (MSCs) have the capacity to prevent this uncontrolled inflammation. However, the mechanism for it has not yet been clarified. We and other researchers found that Regulatory T cells (Treg) /T Helper type 17 (Th17) polarization plays an important role in the uncontrolled inflammation of ARDS. As we all know, both Treg and Th17 polarization need Transforming Growth Factor-β (TGF-β). MSC paracrines TGF-β and can regulate the polarization of Treg and Th17. What’s more, according to our preliminary trials, MSC can increase TGF-β level and Treg/Th17 ratio in the lung of ARDS mice. Therefore, we hypothesize that MSC inhibits inflammation of ARDS by inducing Treg/Th17 polarization balance mediated by paracrine TGF-β. In this study, we investigate the role of Treg/Th17 polarization induced by MSC in ARDS and identify its mechinism whether it is associated with the paracrine soluble factors TGF-β in vitro study. What’s more, in vivo mouse model, we inject MSCs through tail vein after LPS-induced lung injury, then we quantify both Treg and Th17 and estimate their function in regulating immune responses, assess the inflammation in lung tissue and also evaluate the injuried lung restoration to demostrate the protective effect of MSC paracrine TGF-β for ARDS.