Introduction Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD. Methods Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA. Results MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls. Conclusion MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD. Data are available upon reasonable request.

中文翻译：

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人间充质基质细胞抑制临床相关肺部感染模型中鸟分枝杆菌的复制

简介 鸟分枝杆菌复合型肺病 (MAC-PD) 迫切需要新的治疗策略。人间充质基质细胞（MSC）可以直接抑制MAC生长，但其对细胞内杆菌的影响尚不清楚。我们研究了人类 MSC 减少 MAC 感染的巨噬细胞和 MAC-PD 小鼠模型中细菌复制和炎症的能力。方法用鸟分枝杆菌Chester菌株感染人单核细胞源性巨噬细胞（MDM）并用人骨髓源性MSC处理。 72 小时时对细胞内和细胞外集落形成单位 (CFU) 进行计数。六周大的雌性 balb/c 小鼠通过雾化 M. avium Chester 进行感染。感染后 21 天和 28 天，小鼠接受 1×106 静脉内人 MSC 或生理盐水对照治疗。感染后42天收获肺、肝和脾进行细菌计数。通过 ELISA 对细胞因子进行定量。结果 MSC 在 72 小时内减少了 MDM 中的细胞内细菌（中位减少 35%，p=0.027）。 MSC 治疗增加了前列腺素 E2 (PGE2) 的细胞外浓度（中位数增加 10.1 倍，p=0.002）并减少肿瘤坏死因子-α（中位数减少 28%，p=0.025）。用塞来昔布抑制环氧化酶 2 (COX-2) 来阻断 MSC PGE2 的产生会消除抗菌作用，而通过添加外源性 PGE2 可以恢复抗菌作用。与对照组相比，MSC 治疗的小鼠肺部 CFU 较低（中位减少 18%，p=0.012），但脾脏或肝脏 CFU 没有显着变化。结论 在慢性 MAC-PD 小鼠模型中，MSC 可以通过 COX-2/PGE2 信号调节炎症并减少人巨噬细胞内鸟分枝杆菌的生长，并抑制肺部细菌复制。数据可根据合理要求提供。