title: Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo.
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.
authors.affiliation: 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.
authors.forename: Michael C W
authors.initials: MC
authors.lastname: Chan
authors.affiliation: 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;
authors.forename: Denise I T
authors.initials: DI
authors.lastname: Kuok
authors.affiliation: 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;
authors.forename: Connie Y H
authors.initials: CY
authors.lastname: Leung
authors.affiliation: 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;
authors.forename: Kenrie P Y
authors.initials: KP
authors.lastname: Hui
authors.affiliation: 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;
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Valkenburg
authors.affiliation: 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;
authors.forename: Eric H Y
authors.initials: EH
authors.lastname: Lau
authors.affiliation: 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;
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fang
authors.affiliation: 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;
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143; Department of Anesthesiology and Medicine, University of California, San Francisco, CA 94143;
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: 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;
authors.forename: Renee W Y
authors.initials: RW
authors.lastname: Chan
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 malik@hku.hk mchan@hku.hk robert.webster@stjude.org.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143; Department of Anesthesiology and Medicine, University of California, San Francisco, CA 94143;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: 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.
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000803:Angiotensin I / Q000096:biosynthesis; D000818:Animals; D001826:Body Fluids / Q000502:physiology; D018920:Coculture Techniques; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000096:biosynthesis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000150:complications*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000628:therapy; D010539:Permeability; D011650:Pulmonary Alveoli / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D016207:Cytokines; C496453:FGF7 protein, human; D018836:Inflammation Mediators; D051523:Fibroblast Growth Factor 7; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000803:Angiotensin I; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: acute lung injury; alveolar fluid clearance; avian; influenza; mesenchymal stromal cells