Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
Orbsen Therapeutics Ltd, National University of Ireland, Galway, Ireland.
Thorax. 2015 Jul;70(7):625-35. doi: 10.1136/thoraxjnl-2015-206813. Epub 2015 May 18.
Mesenchymal stromal cells (MSCs) demonstrate considerable promise in preclinical acute respiratory distress syndrome models. We wished to determine the efficacy and mechanisms of action of human MSCs (hMSCs) in the setting of acute lung injury induced by prolonged Escherichia coli pneumonia in the rat.
Adult male Sprague Dawley rats underwent intratracheal instillation of E. coli bacteria in all experiments. In Series 1, animals were randomised to intravenous administration of: (1) vehicle (phosphate buffered saline (PBS), 300 μL); (2) 1×10(7) fibroblasts/kg; (3) 1×10(7) hMSCs/kg or (4) 2×10(7) hMSCs/kg. Series 2 determined the lowest effective hMSC dose. Series 3 compared the efficacy of intratracheal versus intravenous hMSC administration, while Series 4 examined the efficacy of cryopreserved hMSC. Series 5 examined the efficacy of the hMSC secretome. Parallel in vitro experiments further assessed the potential for hMSCs to secrete LL-37 and modulate macrophage phagocytosis.
hMSC therapy reduced the severity of rodent E. coli pneumonia, improving survival, decreasing lung injury, reducing lung bacterial load and suppressing inflammation. Doses as low as 5×10(6) hMSCs/kg were effective. Intratracheal hMSC therapy was as effective as intravenous hMSC. Cryopreserved hMSCs were also effective, while the hMSC secretome was less effective in this model. hMSC therapy enhanced macrophage phagocytic capacity and increased lung and systemic concentrations of the antimicrobial peptide LL37.
hMSC therapy decreased E. coli induced pneumonia injury and reduced lung bacterial burden, potentially via enhanced macrophage phagocytosis and increased alveolar LL-37 concentrations.
间充质基质细胞（MSCs）在临床前急性呼吸窘迫综合征模型中表现出相当大的潜力。我们希望确定人 MSCs（hMSCs）在大鼠大肠埃希氏菌肺炎引起的急性肺损伤中的疗效和作用机制。
成年雄性 Sprague Dawley 大鼠在所有实验中均接受气管内滴注大肠埃希氏菌细菌。在系列 1 中，动物随机接受静脉内给予：（1）载体（磷酸盐缓冲盐水（PBS），300μL）；（2）1×10（7）成纤维细胞/kg；（3）1×10（7）hMSCs/kg 或（4）2×10（7）hMSCs/kg。系列 2 确定了最低有效 hMSC 剂量。系列 3 比较了气管内与静脉内 hMSC 给药的疗效，而系列 4 研究了冷冻保存 hMSC 的疗效。系列 5 研究了 hMSC 分泌组的疗效。平行的体外实验进一步评估了 hMSCs 分泌 LL-37 和调节巨噬细胞吞噬作用的潜力。
hMSC 治疗降低了大鼠大肠埃希氏菌肺炎的严重程度，提高了生存率，减轻了肺损伤，降低了肺细菌负荷并抑制了炎症。低至 5×10（6）hMSCs/kg 的剂量有效。气管内 hMSC 治疗与静脉内 hMSC 治疗同样有效。冷冻保存的 hMSCs 也是有效的，而在这种模型中，hMSC 分泌组的效果较差。hMSC 治疗增强了巨噬细胞的吞噬能力，并增加了肺和系统中的抗菌肽 LL37 浓度。
hMSC 治疗减少了大肠埃希氏菌诱导的肺炎损伤并降低了肺部细菌负担，可能通过增强巨噬细胞的吞噬作用和增加肺泡 LL-37 浓度来实现。
