Human Mesenchymal Stem Cells Overexpressing the IL-33 Antagonist Soluble IL-1 Receptor-Like-1 Attenuate Endotoxin-Induced Acute Lung Injury
Human Mesenchymal Stem Cells Overexpressing the IL-33 Antagonist Soluble IL-1 Receptor-Like-1 Attenuate Endotoxin-Induced Acute Lung Injury
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DOI：
10.1165/rcmb.2012-0406oc
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发表时间：
2013-10-01
影响因子：
6.4
通讯作者：
Aran, Josep M.
中科院分区：
文献类型：
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作者：
Martinez-Gonzalez, Itziar;Roca, Oriol;Aran, Josep M.
急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)以肺泡上皮-间质-内皮细胞损伤所致的肺水肿为特征，并伴有严重的炎症和呼吸功能障碍。IL-33/IL-1受体样受体-1(ST2)轴在肺免疫炎症反应的发生中起关键作用。近年来，细胞治疗被认为是治疗ALI和ARDS的一种有效的替代方法。在这里，我们将人脂肪组织来源的间充质干细胞(HASCs)改造成高表达IL-1受体样受体(Sst2)的人脂肪组织间充质干细胞(HASCs)，Sst2是IL-33的诱骗受体，用于小鼠ALI模型时，旨在增强其免疫调节和抗炎特性。在已经出现病变的情况下，我们在内毒素滴入后6h系统地给予hASCs和HASC-Sst2。生物发光成像、免疫组织化学和聚焦转录图谱证实，内毒素攻击后48小时，受损肺中hASCs的存在增加，这些细胞中的免疫调节程序(CXCR-4、肿瘤坏死因子刺激基因6蛋白和吲哚胺2，3-双加氧酶上调)被激活。对hASCs和HASC-Sst2作用的比较评估显示，HASC-Sst2局部过量产生Sst2进一步阻止了IL-33、Toll样受体-4、IL-1β和干扰素-γ的诱导，但增加了IL-10在损伤肺中的表达。这种协同作用导致肺空隙炎症和血管渗漏显著减少，其特征是蛋白质含量、中性粒细胞分类计数和支气管肺泡灌洗液中促炎症细胞因子(TNF-α、IL-6和巨噬细胞炎症蛋白2)浓度显著降低。此外，HASC-Sst2治疗的ALI肺显示出保留的肺泡结构，没有细胞凋亡，以及最少的炎细胞浸润。这些结果表明，通过基因工程产生Sst2的hASCs可能成为ALI/ARDS治疗的一种有前途的治疗策略。
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by pulmonary edema attributable to alveolar epithelial-interstitial-endothelial injury, associated with profound inflammation and respiratory dysfunction. The IL-33/IL-1 receptor-like-1 (ST2) axis plays a key role in the development of immuneinflammatory responses in the lung. Cell-based therapy has been recently proposed as an effective alternative for the treatment of ALI and ARDS. Here, we engineered human adipose tissue-derived mesenchymal stem cells (hASCs) overexpressing soluble IL-1 receptor-like-1 (sST2), a decoy receptor for IL-33, in order to enhance their immunoregulatory and anti-inflammatory properties when applied in a murine ALI model. We administered both hASCs and hASC-sST2 systemically at 6 hours after intranasal LPS instillation, when pathological changes had already occurred. Bioluminescence imaging, immunohistochemistry, and focused transcriptional profiling confirmed the increased presence of hASCs in the injured lungs and the activation of an immunoregulatory program (CXCR-4, tumor necrosis factor-stimulated gene 6 protein, and indoleamine 2,3-dioxygenase up-regulation) in these cells, 48 hours after endotoxin challenge. A comparative evaluation of hASCs and the actions of hASC-sST2 revealed that local sST2 overproduction by hASC-sST2 further prevented IL-33, Toll-like receptor-4, IL-1 beta, and IFN-gamma induction, but increased IL-10 expression in the injured lungs. This synergy caused a substantial decrease in lung airspace inflammation and vascular leakage, characterized by significant reductions in protein content, differential neutrophil counts, and proinflammatory cytokine (TNF-alpha, IL-6, and macrophage inflammatory protein 2) concentrations in bronchoalveolar lavage fluid. In addition, hASC-sST2-treatedALI lungs showed preserved alveolar architecture, an absence of apoptosis, and minimal inflammatory cell infiltration. These results suggest that hASCs genetically engineered to produce sST2 could become a promising therapeutic strategy for ALI/ARDSmanagement.