title: Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat.
abstract: BACKGROUND
  Mesenchymal stromal cells (MSCs) demonstrate considerable promise in preclinical acute respiratory distress syndrome models. We wished to determine the efficacy and mechanisms of action of human MSCs (hMSCs) in the setting of acute lung injury induced by prolonged Escherichia coli pneumonia in the rat.
  
  
  METHODS
  Adult male Sprague Dawley rats underwent intratracheal instillation of E. coli bacteria in all experiments. In Series 1, animals were randomised to intravenous administration of: (1) vehicle (phosphate buffered saline (PBS), 300 μL); (2) 1×10(7) fibroblasts/kg; (3) 1×10(7) hMSCs/kg or (4) 2×10(7) hMSCs/kg. Series 2 determined the lowest effective hMSC dose. Series 3 compared the efficacy of intratracheal versus intravenous hMSC administration, while Series 4 examined the efficacy of cryopreserved hMSC. Series 5 examined the efficacy of the hMSC secretome. Parallel in vitro experiments further assessed the potential for hMSCs to secrete LL-37 and modulate macrophage phagocytosis.
  
  
  RESULTS
  hMSC therapy reduced the severity of rodent E. coli pneumonia, improving survival, decreasing lung injury, reducing lung bacterial load and suppressing inflammation. Doses as low as 5×10(6) hMSCs/kg were effective. Intratracheal hMSC therapy was as effective as intravenous hMSC. Cryopreserved hMSCs were also effective, while the hMSC secretome was less effective in this model. hMSC therapy enhanced macrophage phagocytic capacity and increased lung and systemic concentrations of the antimicrobial peptide LL37.
  
  
  CONCLUSIONS
  hMSC therapy decreased E. coli induced pneumonia injury and reduced lung bacterial burden, potentially via enhanced macrophage phagocytosis and increased alveolar LL-37 concentrations.
authors.affiliation: Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Devaney
authors.affiliation: Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Shahd
authors.initials: S
authors.lastname: Horie
authors.affiliation: Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Masterson
authors.affiliation: Orbsen Therapeutics Ltd, National University of Ireland, Galway, Ireland.
authors.forename: Steve
authors.initials: S
authors.lastname: Elliman
authors.affiliation: Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Frank
authors.initials: F
authors.lastname: Barry
authors.affiliation: Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Department of Anesthesia, Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Curley
authors.affiliation: Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.affiliation: Department of Anesthesia, Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Laffey
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D058491:Bacterial Load; D015925:Cryopreservation; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D006801:Humans; D007262:Infusions, Intravenous; D007442:Intubation, Intratracheal; D008168:Lung / Q000382:microbiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D010587:Phagocytosis; D018410:Pneumonia, Bacterial / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous
keywords: ARDS; Bacterial Infection