Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Am J Pathol. 2011 Sep;179(3):1088-94. doi: 10.1016/j.ajpath.2011.05.027. Epub 2011 Jul 8.
Acute respiratory distress syndrome (ARDS) is a crippling disease with no effective therapy characterized by progressive dyspnea. Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for ARDS because MSCs can attenuate inflammation and repair the damaged tissue by differentiating into several cell types. Macrophages participate in the development of ARDS; however, MSCs only weakly modulate macrophage function. The chemokine CCL2 is a potent inducer of macrophage recruitment and activation, and its expression is elevated in patients with ARDS. We established MSCs that are stably transduced by a lentiviral vector expressing 7ND, a dominant-negative inhibitor of CCL2, to enhance the therapeutic function of MSCs. 7ND-MSCs retained the innate properties of MSCs and produced a large amount of 7ND. Many 7ND-MSCs were detected in bleomycin-treated lungs (immunostaining 24 hours after injection), suggesting that MSCs could work as a drug delivery tool. Mice treated with 7ND-MSCs showed significantly milder weight loss, lung injury, collagen content, accumulation of inflammatory cells and inflammatory mediators that were induced by bleomycin, and subsequent survival benefit. No evidence of 7ND-MSC-induced toxicity was observed during or after treatment. Thus, inhibiting the effects of macrophages may greatly enhance the ability of MSCs to effect lung repair in ARDS.
急性呼吸窘迫综合征（ARDS）是一种致残性疾病，没有有效的治疗方法，其特征是进行性呼吸困难。间充质干细胞（MSCs）作为 ARDS 的一种新的治疗方法出现，因为 MSCs 可以通过分化为多种细胞类型来减轻炎症和修复受损组织。巨噬细胞参与 ARDS 的发生；然而，MSCs 对巨噬细胞功能的调节作用较弱。趋化因子 CCL2 是巨噬细胞募集和激活的有力诱导剂，其在 ARDS 患者中的表达水平升高。我们建立了稳定转导慢病毒载体表达 7ND 的 MSCs，7ND 是 CCL2 的显性负性抑制剂，以增强 MSCs 的治疗功能。7ND-MSCs 保留了 MSCs 的固有特性，并产生大量 7ND。在博莱霉素处理的肺中（注射后 24 小时免疫染色）检测到许多 7ND-MSCs，表明 MSCs 可以作为药物输送工具。用 7ND-MSCs 治疗的小鼠表现出明显较轻的体重减轻、肺损伤、胶原含量、炎症细胞和炎症介质的积累，以及博莱霉素诱导的随后的生存获益。在治疗过程中或之后没有观察到 7ND-MSC 诱导的毒性的证据。因此，抑制巨噬细胞的作用可能极大地增强 MSCs 在 ARDS 中修复肺的能力。
