PAI-1参与MSCs微环境调控在肺缺血再灌注损伤修复中的机制

项目名称： PAI-1参与MSCs微环境调控在肺缺血再灌注损伤修复中的机制

项目编号： No.81200051

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 佘君

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 缺血再灌注损伤（IRI）是早期肺移植后死亡的主要原因。肺IRI以毛细血管弥漫性损伤，通透性增加为主要病理表现。我们的研究显示，间充质干细胞（MSCs）通过旁分泌活性物质-角质细胞生长因子(KGF)，抑制纤溶酶原活化抑制因子(PAI)-1，进而阻止低氧所致肺微血管内皮的高通透性，显示了强大的修复潜能。然而MSCs的低存活率限制其在肺损伤修复中的应用。目前认为，PAI-1是MSCs体内存活的负调节因子，但PAI-1如何参与MSCs微环境调控尚不清楚。本研究应用PAI-1抑制剂和PAI-1基因剔除小鼠，从细胞和动物水平，探讨PAI-1在肺缺血再灌注损伤致微血管内皮通透性变化的分子机制；解析MSCs通过KGF与微血管内皮细胞的互动作用和PAI-1的关系；探索PAI-1参与MSCs信号递送和线粒体功能的调控。本研究可丰富MSCs理论，为治疗肺移植导致的急性肺损伤提供新思路和靶点。

中文关键词： 自噬；骨髓间充质干细胞；肺损伤；；

英文摘要： Ischemia-reperfusion injury (IRI) is the early leading cause of mortality and morbidity after lung transplantation. The Main pathology of lung IRI is the high permeability due to diffuse injury in capillary. Our preliminary study showed mesenchymal stem cells (MSCs) paracrine activity factor-keratinocyte growth factor (KGF) could prevent the hypoxia-induced pulmonary injury by inhibition of plasminogen activator inhibitor-1(PAI-1), which displayed the potential of lung injury repair. However, the low survival of transplanted MSCs precludes the overall effectiveness and significantly affects clinical usage in the treatment of lung injury. PAI-1 has been reported as a negative regulator of MSCs survival in vivo, while the detailed mechanisms of PAI-1 regulating the MSCs in micro-environment remain unclear. In the present study, by using PAI-1 inhibitor and PAI-1 knockout mice in vivo and vitro, we will determine the effects of PAI-1 on microvascular endothelial permeability in IRI. Then, we will study that PAI-1 may be associated with KGF to participate in the reciprocal interaction between MSCs and endothelial cells in the lung. Finally, we postulate PAI-1 is involved in the regulation of signal delivery and mitochondrial function for MSCs exposure to hypoxia and nutrient-poor environmental stress. Base on these

英文关键词： Autophagy；Bone marrow-derived mesenchymal stem cell；Lung injury；；