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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3621-6. doi: 10.1073/pnas.1601911113. Epub 2016 Mar 14.

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo.

Author information

1
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; malik@hku.hk mchan@hku.hk robert.webster@stjude.org.
2
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;
3
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;
4
Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
5
Cardiovascular Research Institute, University of California, San Francisco, CA 94143; Department of Anesthesiology and Medicine, University of California, San Francisco, CA 94143;
6
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 Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China;
7
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 malik@hku.hk mchan@hku.hk robert.webster@stjude.org.

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.

KEYWORDS:

acute lung injury; alveolar fluid clearance; avian; influenza; mesenchymal stromal cells

PMID:
26976597
PMCID:
PMC4822574
DOI:
10.1073/pnas.1601911113
[Indexed for MEDLINE]
Free PMC Article

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