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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / etiology
  • Acute Lung Injury / physiopathology
  • Acute Lung Injury / prevention & control*
  • Angiotensin I / biosynthesis
  • Animals
  • Body Fluids / physiology
  • Coculture Techniques
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Cytokines / biosynthesis
  • Female
  • Fibroblast Growth Factor 7 / biosynthesis
  • Humans
  • Inflammation Mediators / metabolism
  • Influenza A Virus, H5N1 Subtype / pathogenicity*
  • Influenza, Human / complications*
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Orthomyxoviridae Infections / complications*
  • Orthomyxoviridae Infections / therapy
  • Permeability
  • Pulmonary Alveoli / physiopathology
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • CFTR protein, human
  • Cytokines
  • FGF7 protein, human
  • Inflammation Mediators
  • Fibroblast Growth Factor 7
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Angiotensin I
  • ATP1A1 protein, human
  • Sodium-Potassium-Exchanging ATPase