老化对间充质干细胞在急性肺损伤中作用的影响

The incidence of severe acute lung injury (acute respiratory distress syndrome- - -ARDS) increases with age. Mortality in acute lung injury is also higher in older patients.Aging is accompanied by an increased inflammatory response and a reduction in quality and quantity of bone marrow stem cells. Recent studies from our group and others have shown that mesenchymal stem cells (MSCs) attenuate the lung injury induced by LPS. We also reported that aged animals are more susceptible to lung injury. In this grant application, I propose that aging affects the role of MSCs in acute lung injury (Hypotheis 1). The prevailing hypothesis for the effect of MSCs is that MSCs produce cytokines through paracrine effect, which in turn moderate lung injury. Here, I propose a brand new idea that MSCs directly modulate M2 macrophage activation during lung injury and the process is affected by aging (Hypothesis 2). Based on the beneficial results from clinical trials in other disease states, I also propose to determine whether MSCs from young donors might be a useful therapeutic tool for aged persons with ARDS (Hypothesis 3). The proposed studies may provide new insights into the mechanisms of acute lung injury and may also reveal a new strategy for treating ARDS.

急性肺损伤（急性呼吸窘迫综合征,ARDS）的发病率随着年龄增长而上升。老年人发生ARDS的死亡率更高。老龄化伴随着增加的炎症反应和骨髓干细胞的质量和数量的减少。我们研究小组在国际上最先报道了，骨髓间充质干细胞（MSCs）可减轻LPS诱导的肺损伤。我们还报告，快速老化小鼠更易受肺损伤。在此项申请中，我假设老化影响MSCs在急性肺损伤中的作用 (假设 1) 。目前关于MSCs作用普遍认同的机理是MSCs产生细胞因子，通过旁分泌作用从而调节肺损伤。在本课题，我提出了一个全新的假设，既在急性肺损伤过程中MSCs 通过直接调节M2巨噬细胞活化而发生作用, 而这调节作用受老龄化的影响（假设2）。根据MSCs 在其他疾病的临床试验结果，我再假设移植年轻捐赠者的骨髓MSCs可能是一种对老年ARDS患者有用的治疗手段（假设3）。我提出的研究可能会对急性肺损伤机制提供新的见解，也可能揭示治疗ARDS的新手段。

急性肺损伤（急性呼吸窘迫综合症ARDS）是严重威胁患者生命的常见临床危急重症。其起病急骤、病情凶险、死亡率高。急性肺损伤的发病率随着年龄的增长而上升，老年人发生ARDS的死亡率更高。本课题组应用已建立的间充质干细胞在急性肺损伤研究的良好平台，在国家自然科学基金资助下，我们首次报道脂肪间充质干细胞（ASCs）驯化的巨噬细胞能通过IL-10直接改善LPS诱导的全身炎症反应。老化影响ASCs 上调M2型巨噬细胞从而影响急性肺损伤。我们也首次报道了间充质干细胞在ARDS的临床试验结果，本文献被同行大量引用。在完成本课题之外，我们还发现ASCs通过COX-2-PGE2通路调节脓毒症患者外周血单核细胞CD14++CD16+的表达及功能。

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