Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy
Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy
复制标题
DOI：
10.1152/ajplung.00110.2014
复制
发表时间：
2014-09-01
影响因子：
4.9
通讯作者：
Matthay, Michael A.
中科院分区：
文献类型：
--
作者：
Gotts, Jeffrey E.;Abbott, Jason;Matthay, Michael A.
病毒性肺炎是急性呼吸窘迫综合征（ARDS）的主要原因。病毒诱导的肺损伤的抗炎治疗在临床前模型中显示出希望。间充质干/基质细胞（MSC）是多能的、自我更新的细胞，其分泌抗炎细胞因子以及上皮和内皮生长因子。我们用流感A（鼠适应的波多黎各/8/34）或PBS鼻内接种小鼠，并且在感染后的多个时间点处死小鼠以测量肺损伤和病毒载量。我们报告说，流感诱导明显的，长期的肺泡毛细血管屏障功能障碍，在1周达到峰值，但持续时间超过3周感染后。体重减轻，通常被用作安乐死的标准（因此是“生存”），被发现在其高峰期对肺损伤的严重程度预测性很差;相反，感染后11天的持续体重减轻确定了损伤消退受损的小鼠。然后在损伤进展的快速阶段静脉内施用小鼠和人骨髓来源的MSC（从国立卫生研究院储存库获得）。小鼠间充质干细胞（mMSCs）给予两次，间隔24小时，未能改善体重减轻，肺水，支气管肺泡灌洗炎症，或组织学。然而，mMSC预防流感诱导的血小板增多，并在第7天引起肺病毒载量的适度降低。静脉内施用的人MSC显示出类似的缺乏功效。结果表明，流感鼠模型与患者中ARDS的缓慢消退具有重要的相似性。尽管MSC在许多急性炎症和肺损伤模型中具有有效的治疗作用，但它并不能改善小鼠流感介导的肺损伤。
Viral pneumonia is a major cause of acute respiratory distress syndrome (ARDS). Anti-inflammatory therapies for viral-induced lung injury show promise in preclinical models. Mesenchymal stem/stromal cells (MSCs) are multipotent, self-renewing cells that secrete anti-inflammatory cytokines and epithelial and endothelial growth factors. We inoculated mice intranasally with influenza A (murine-adapted Puerto Rico/8/34) or PBS, and the mice were killed at multiple time points after infection for measures of lung injury and viral load. We report that influenza induces marked, long-lasting dysfunction of the alveolar-capillary barrier peaking at 1 wk but lasting longer than 3 wk postinfection. Weight loss, commonly employed as a criterion for euthanasia (and hence "survival"), was found to be poorly predictive of the severity of lung injury at its peak; rather, persistent weight loss 11 days postinfection identified mice with impaired injury resolution. Murine and human bone marrow-derived MSCs (obtained from the National Institutes of Health repository) were then administered intravenously during the rapid phase of injury progression. Murine MSCs (mMSCs) given two times 24 h apart failed to improve weight loss, lung water, bronchoalveolar lavage inflammation, or histology. However, mMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load at day 7. Human MSCs administered intravenously showed a similar lack of efficacy. The results demonstrate that the influenza murine model bears important similarities to the slow resolution of ARDS in patients. Despite their potent therapeutic effects in many models of acute inflammation and lung injury, MSCs do not improve influenza-mediated lung injury in mice.