Wang Chenfei, Lv Dan, Zhang Xiaobin, Ni Zhu-Ang, Sun Xiaofan, Zhu Changqing
1 Department of Emergency, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
2 Department of Outpatient and Emergency, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
DNA Cell Biol. 2018 Jan;37(1):53-61. doi: 10.1089/dna.2017.3735. Epub 2017 Oct 26.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening inflammatory conditions with no effective pharmacological treatment. Previous studies suggested that mesenchymal stromal/stem cell (MSC) infusion resulted in better survival in mouse ALI models and presented low toxicity in human subjects. Therefore, in this study, we investigated the possibility of treating a murine model of ALI using MSCs with constant interleukin-10 overexpression (IL-10-MSC) by retroviral infection. ALI in mice was induced by intratracheal lipopolysaccharides (LPS) instillation. After 96 h, 80% of mice receiving IL-10-MSCs survived, whereas the survival rate of the mice receiving other treatments was only 20-50%. Mice receiving IL-10-MSCs also demonstrated significantly less weight loss (p < 0.01), and lower protein level and TNF concentration in the BAL (p < 0.01). Interestingly, IL-10-MSCs given to mice 3 and 1 day before ALI induction still conferred significant protection against ALI. While direct IL-10 transfusion resulted in an intensive, but transient peak in serum IL-10 level, IL-10-MSCs provided a milder, but more persistent increase in serum IL-10 level, together with significantly higher levels of IL-10-producing T cells and B cells, both in the spleen and in the lung. IL-10-MSCs given 3 days before LPS challenge resulted in higher pulmonary infiltration of IL-10-producing T cells and B cells in mice. On average, mice that survived the LPS challenge for 96 h presented higher pulmonary infiltration of IL-10-producing T cells and B cells than mice that deceased within the experimental period. Together, these results demonstrated that IL-10-MSCs offered superior protection against LPS-induced ALI when given before or at the time of ALI induction, and significantly increased the frequencies of IL-10-expressing T cells and B cells. IL-10-MSCs may thus represent a promising new treatment option in ALI/ARDS.
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是危及生命的炎症性病症，目前尚无有效的药物治疗方法。先前的研究表明，间充质基质/干细胞（MSC）输注可提高小鼠ALI模型的存活率，且在人体中显示出低毒性。因此，在本研究中，我们通过逆转录病毒感染，研究了使用持续过表达白细胞介素-10（IL-10-MSC）的间充质干细胞治疗小鼠ALI模型的可能性。通过气管内滴注脂多糖（LPS）诱导小鼠发生ALI。96小时后，接受IL-10-MSC治疗的小鼠80%存活，而接受其他治疗的小鼠存活率仅为20%-50%。接受IL-10-MSC治疗的小鼠体重减轻也显著更少（p<0.01），支气管肺泡灌洗液（BAL）中的蛋白质水平和肿瘤坏死因子浓度更低（p<0.01）。有趣的是，在ALI诱导前3天和1天给予小鼠IL-10-MSC，仍能对ALI提供显著保护。直接输注IL-10会导致血清IL-10水平出现强烈但短暂的峰值，而IL-10-MSC则使血清IL-10水平出现较温和但更持久的升高，同时脾脏和肺中产生IL-10的T细胞和B细胞水平显著更高。在LPS攻击前3天给予IL-10-MSC可使小鼠肺部产生IL-10的T细胞和B细胞浸润增加。平均而言，在LPS攻击后存活96小时的小鼠肺部产生IL-10的T细胞和B细胞浸润高于在实验期内死亡的小鼠。总之，这些结果表明，在ALI诱导前或诱导时给予IL-10-MSC可对LPS诱导的ALI提供更好的保护，并显著增加表达IL-10的T细胞和B细胞的频率。因此，IL-10-MSC可能是ALI/ARDS一种有前景的新治疗选择。
