Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria
Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria
复制标题
人间充质干细胞对活细菌损伤的离体人肺的治疗作用
DOI：
10.1164/rccm.201206-0990oc
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发表时间：
2013-04-01
影响因子：
24.7
通讯作者：
Matthay, Michael A.
中科院分区：
文献类型：
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作者：
Lee, Jae W.;Krasnodembskaya, Anna;Matthay, Michael A.
理由：间充质干细胞分泌的旁分泌因子可以调节肺通透性和减少炎症，使其成为治疗急性肺损伤的潜在吸引力。然而，如果将间充质干细胞的免疫调节特性用于肺损伤的感染性病因，是否会产生有害影响仍值得关注。目的：因此，我们测试了间充质干细胞对肺液平衡、急性炎症和细菌清除的影响。方法：建立离体灌注人肺大肠杆菌肺炎模型，观察间充质干细胞对细菌性急性肺损伤的治疗作用。测量结果和主要结果：临床级人间充质干细胞将肺泡液清除率恢复到正常水平，减少炎症，并与增加的细菌杀伤和减少的菌血症相关，部分原因是通过增加肺泡巨噬细胞吞噬和抗菌因子的分泌。角质细胞生长因子是一种由间充质干细胞分泌的可溶性因子，它复制了大部分的抗菌作用。在随后的体外研究中，我们发现人单核细胞表达角化细胞生长因子受体，角化细胞生长因子通过AKT磷酸化减少人单核细胞的凋亡，这一作用增加了细菌清除率。中和抗体抑制角质细胞生长因子可降低体外灌注的人肺和体外培养的单核细胞间充质干细胞的抗菌作用。结论：在大肠杆菌损伤的人肺中，间充质干细胞恢复肺泡液清除，减少炎症，并发挥抗菌活性，部分通过角化细胞生长因子的分泌。
Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells' immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury.Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance.Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury.Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria.Conclusions: In E. coli injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.