Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesized that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from patients with ARDS were segregated into hypo- and hyper-inflammatory categories based on interleukin (IL)-6 levels. MSCs were licensed with pooled serum from patients with hypo- or hyper-inflammatory ARDS or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSC-CM) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells and in a vascular endothelial growth factor (VEGF)-dependent manner. Importantly, while both MSC-CM and MSC-CM significantly reduced IL-6 and tumor necrosis factor alpha (TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI mice, only MSC-CM significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus, the hypo- and hyper-inflammatory ARDS environments may differentially influence MSC cytoprotective and immunomodulatory functions.

中文翻译：

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ARDS 微环境在实验性急性肺部炎症中通过 VEGF 增强 MSC 诱导的修复


调查间充质基质细胞 （MSCs） 治疗炎症性疾病（如急性呼吸窘迫综合征 （ARDS））潜力的临床试验令人失望，只有不到 50% 的患者对治疗有反应。获得许可的 MSC 在响应细胞因子介导的激活信号时显示出增强的治疗效果。ARDS 有两种不同的亚表型：低炎症和高炎症。我们假设在高度炎症性 ARDS 环境中预先许可 MSC 将增强其在急性肺部炎症 （ALI） 中的治疗效果。根据白细胞介素 （IL）-6 水平将 ARDS 患者的血清样本分为低炎症和高炎症类别。MSC 获得许可使用来自低炎症或高度炎症 ARDS 患者或健康血清对照的混合血清。我们的研究结果表明，高炎性 ARDS 预许可的 MSC 条件培养基 （MSC-CM） 导致肺上皮细胞和血管内皮生长因子 （VEGF） 依赖性方式的紧密连接表达显着富集和屏障完整性增强。重要的是，虽然 MSC-CM 和 MSC-CM 均显著降低脂多糖 （LPS） 诱导的 ALI 小鼠支气管肺泡灌洗液 （BALF） 中的 IL-6 和肿瘤坏死因子 α （TNF-α） 水平，但只有 MSC-CM 显著降低肺通透性和总体临床结局，包括体重减轻和临床评分。因此，低炎性和高炎性 ARDS 环境可能对 MSC 细胞保护和免疫调节功能产生不同的影响。