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Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo
Significance
Acute lung injury, including impaired alveolar fluid clearance, is a life-threatening complication of severe respiratory virus infection, and effective treatment is lacking. Understanding the mechanism of this complication may suggest novel therapies. Here, we found that, in vitro, influenza A/H5N1 infection impaired alveolar fluid clearance more than did seasonal virus, mimicking its greater severity in patients. We demonstrated that this impairment is mediated by the release of soluble factors from infected cells, leading to down-regulation of alveolar sodium and chloride transporters. Mesenchymal stromal cells prevented or reduced this effect in vitro and in vivo in A/H5N1-infected mice. These cells provide a potentially effective treatment for acute lung injury in severe influenza.
Abstract
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.
- Michael C. W. Chana,1,
- Denise I. T. Kuoka,
- Connie Y. H. Leunga,
- Kenrie P. Y. Huia,
- Sophie A. Valkenburga,
- Eric H. Y. Laua,
- John M. Nichollsb,
- Xiaohui Fangc,
- Yi Guana,
- Jae W. Leec,d,
- Renee W. Y. Chana,e,
- Robert G. Websterf,1,
- Michael A. Matthayc,d, and
- J. S. Malik Peirisa,1
- aCentre 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;
- bDepartment 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;
- cCardiovascular Research Institute, University of California, San Francisco, CA 94143;
- dDepartment of Anesthesiology and Medicine, University of California, San Francisco, CA 94143;
- eDepartment of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People?s Republic of China;
- fDepartment of Infectious Diseases, St. Jude Children?s Research Hospital, Memphis, TN 38105
- Contributed by Robert G. Webster, February 13, 2016 (sent for review August 24, 2015; reviewed by Peter J. Openshaw, Luis Ortiz, and Daniel Perez)
Significance
Acute lung injury, including impaired alveolar fluid clearance, is a life-threatening complication of severe respiratory virus infection, and effective treatment is lacking. Understanding the mechanism of this complication may suggest novel therapies. Here, we found that, in vitro, influenza A/H5N1 infection impaired alveolar fluid clearance more than did seasonal virus, mimicking its greater severity in patients. We demonstrated that this impairment is mediated by the release of soluble factors from infected cells, leading to down-regulation of alveolar sodium and chloride transporters. Mesenchymal stromal cells prevented or reduced this effect in vitro and in vivo in A/H5N1-infected mice. These cells provide a potentially effective treatment for acute lung injury in severe influenza.
Abstract
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.
