Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro. When administered in vivo, MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.

尽管间充质基质（干）细胞（MSC）给药可以减轻临床前模型中脓毒症引起的肺损伤，但其作用机制和宿主免疫系统对其治疗效果的贡献仍然难以捉摸。我们发现，在脓毒症小鼠的肺中，用 MSC 治疗可降低宿主来源的 microRNA (miR)-193b-5p 的表达，并增加其靶基因紧密连接蛋白 occludin (Ocln) 的表达。突变 Ocln 3' 非翻译区 miR-193b-5p 结合序列会损害与 Ocln mRNA 的结合。抑制人原代肺微血管内皮细胞中的 miR-193b-5p 可防止肿瘤坏死因子 (TNF) 诱导的 Ocln 基因和蛋白表达下降以及屏障功能丧失。MSC 条件培养基在体外减轻了 TNF 诱导的 miR-193b-5p 上调和 Ocln 下调。当体内给药时，MSC 条件培养基重现了 MSC 给药对肺 miR-193b-5p 和 Ocln 表达的影响。MiR-193b 缺陷小鼠对脂多糖 (LPS) 滴注诱导的肺部炎症和损伤具有抵抗力。miR-193b 缺陷小鼠中 Ocln 的沉默部分恢复了对 LPS 诱导的肺损伤的易感性。体内抑制 miR-193b-5p 可保护小鼠免受内毒素诱导的肺损伤。最后，死于弥漫性肺泡损伤的急性呼吸窘迫综合征患者的肺尸检样本中发现 miR-193b-5p 表达水平增加，支持了这些结果的临床意义。