Chan Michael C W, Kuok Denise I T, Leung Connie Y H, Hui Kenrie P Y, Valkenburg Sophie A, Lau Eric H Y, Nicholls John M, Fang Xiaohui, Guan Yi, Lee Jae W, Chan Renee W Y, Webster Robert G, Matthay Michael A, Peiris J S Malik
Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China;
Department of Pathology, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China;
Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3621-6. doi: 10.1073/pnas.1601911113. Epub 2016 Mar 14.
Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.
流感可导致急性肺损伤。由于免疫反应通常起作用，抗病毒药物可能无法确保取得成功的治疗效果。为了确定致病机制和潜在的辅助治疗选择，我们在急性肺损伤的体外模型中比较了甲型H5N1禽流感病毒和季节性甲型H1N1流感病毒对肺泡液体清除和蛋白质通透性的损害程度，确定了病毒诱导的可溶性介质在这些损伤效应中的作用，并证明骨髓来源的多能间充质基质细胞可预防或减轻这些效应。我们在实验感染甲型H5N1流感病毒的小鼠中验证了这些发现的体内相关性。我们发现，在体外，感染禽流感病毒（A/香港/483/97，H5N1）而非季节性流感病毒（A/香港/54/98，H1N1）后释放的可溶性免疫介质会使肺泡上皮的蛋白质通透性和液体清除失调。与钠和氯转运体下调相关的肺泡液体转运减少可通过与间充质基质细胞共培养来预防或减轻。在体内，用间充质基质细胞治疗感染H5N1的老年小鼠可提高其存活几率。我们得出结论，间充质基质细胞可显著减轻体外A/H5N1感染诱导的肺泡液体清除障碍，并在体内预防或减轻A/H5N1相关的急性肺损伤。这种针对严重流感诱导的肺部疾病的潜在辅助治疗方法值得迅速开展临床研究。
