Su Vincent Yi-Fong, Chiou Shih-Hwa, Lin Chi-Shiuan, Chen Wei-Chih, Yu Wen-Kuang, Chen Yen-Wen, Chen Cheng-Yu, Yang Kuang-Yao
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Department of Internal Medicine, Taipei City Hospital, Taipei City Government, Taipei, Taiwan.
Respirology. 2017 Aug;22(6):1156-1164. doi: 10.1111/resp.13053. Epub 2017 Apr 21.
We investigated the effect of induced pluripotent stem cells (iPSCs) in moderating neutrophil chemotaxis in endotoxin-induced acute lung injury (ALI).
Male C57BL/6 mice at 8-12 weeks of age were studied. Murine iPSCs were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathological findings, neutrophil counts in peripheral blood and bronchoalveolar lavage fluid (BALF), bone marrow (BM) cell distribution, expression of chemokine receptors and regulatory signalling pathways were analysed after 24 h. Human neutrophils isolated from acute respiratory distress syndrome patients were used in a cell migration assay.
iPSCs significantly decreased the histopathological changes of ALI in mice compared to treatment with control cells. Numbers and activity levels of neutrophils in BALF were reduced in iPSC-treated ALI mice. The iPSC therapy restored neutrophil counts in the peripheral blood of ALI mice, but the percentages of mature neutrophils in BM were similar between iPSC-treated and -untreated groups. The iPSCs mediated a downregulation of the chemotactic response to endotoxin by reducing chemokine (C-X-C motif) receptor 2 (CXCR2) expression on mouse peripheral blood neutrophils. This result was confirmed by an in vitro human neutrophil migration assay. In addition, iPSCs or conditioned medium from iPSCs enhanced expression of G protein-coupled receptor kinase 2 (GRK2) on the surface of blood neutrophils in ALI mice.
iPSCs reduce neutrophil chemotaxis in endotoxin-induced ALI. These effects are associated with an enhancement of GRK2 activity and reduction of CXCR2 expression.
我们研究了诱导多能干细胞（iPSC）对内毒素诱导的急性肺损伤（ALI）中中性粒细胞趋化性的调节作用。
对8 - 12周龄的雄性C57BL/6小鼠进行研究。在内毒素气管内滴注4小时后，通过小鼠尾静脉注入鼠iPSC。24小时后分析肺组织病理学结果、外周血和支气管肺泡灌洗液（BALF）中的中性粒细胞计数、骨髓（BM）细胞分布、趋化因子受体表达及调节信号通路。使用从急性呼吸窘迫综合征患者分离出的人中性粒细胞进行细胞迁移试验。
与对照细胞治疗相比，iPSC显著减轻了小鼠ALI的组织病理学变化。iPSC治疗的ALI小鼠BALF中中性粒细胞的数量和活性水平降低。iPSC疗法恢复了ALI小鼠外周血中的中性粒细胞计数，但iPSC治疗组和未治疗组BM中成熟中性粒细胞的百分比相似。iPSC通过降低小鼠外周血中性粒细胞上趋化因子（C - X - C基序）受体2（CXCR2）的表达，介导对内毒素趋化反应的下调。体外人中性粒细胞迁移试验证实了这一结果。此外，iPSC或iPSC条件培养基增强了ALI小鼠血液中性粒细胞表面G蛋白偶联受体激酶2（GRK2）的表达。
iPSC可降低内毒素诱导的ALI中的中性粒细胞趋化性。这些作用与GRK活性增强和CXCR2表达降低有关。
