1 Human Molecular Genetics Group, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
Am J Respir Cell Mol Biol. 2013 Oct;49(4):552-62. doi: 10.1165/rcmb.2012-0406OC.
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 immune-inflammatory 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-1β, and IFN-γ 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-α, IL-6, and macrophage inflammatory protein 2) concentrations in bronchoalveolar lavage fluid. In addition, hASC-sST2-treated ALI 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/ARDS management.
急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 的特征是由肺泡上皮-间质-内皮损伤引起的肺水肿，伴有严重的炎症和呼吸功能障碍。IL-33/IL-1 受体样-1 (ST2) 轴在肺部免疫炎症反应的发展中起着关键作用。细胞治疗最近被提出作为治疗 ALI 和 ARDS 的有效替代方法。在这里，我们通过过表达可溶性 IL-1 受体样-1 (sST2) 对人脂肪组织来源的间充质干细胞 (hASC) 进行基因工程改造，sST2 是 IL-33 的诱饵受体，以便在小鼠 ALI 模型中应用时增强其免疫调节和抗炎特性。我们在鼻内 LPS 滴注后 6 小时内系统给予 hASC 和 hASC-sST2 系统，此时已经发生了病理变化。生物发光成像、免疫组织化学和聚焦转录谱分析证实，在脂多糖挑战后 48 小时，hASC 在受损的肺部中存在增加，并在这些细胞中激活了一个免疫调节程序 (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)。hASC 和 hASC-sST2 作用的比较评估表明，hASC-sST2 局部过表达 sST2 进一步阻止了 IL-33、Toll 样受体-4、IL-1β 和 IFN-γ 的诱导，但增加了受损肺部的 IL-10 表达。这种协同作用导致肺空气空间炎症和血管渗漏显著减少，特征是蛋白质含量、中性粒细胞计数和炎症细胞因子 (TNF-α、IL-6 和巨噬细胞炎症蛋白 2) 浓度在支气管肺泡灌洗液中显著降低。此外，hASC-sST2 治疗的 ALI 肺显示出保存的肺泡结构、无细胞凋亡和最小的炎症细胞浸润。这些结果表明，基因工程改造产生 sST2 的 hASC 可能成为治疗 ALI/ARDS 的有前途的治疗策略。
