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Original article
Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat
  1. James Devaney1,2,
  2. Shahd Horie1,2,
  3. Claire Masterson1,2,
  4. Steve Elliman3,
  5. Frank Barry2,
  6. Timothy O'Brien2,
  7. Gerard F Curley4,
  8. Daniel O’Toole1,2,
  9. John G Laffey4
  1. 1Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland
  2. 2Regenerative Medicine Institute, National University of Ireland, Galway, Ireland
  3. 3Orbsen Therapeutics Ltd, National University of Ireland, Galway, Ireland
  4. 4Department of Anesthesia, Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Prof John G Laffey, Department of Anesthesia, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Ontario M5B 1W8, Canada; laffeyj{at}smh.ca, john.laffey{at}nuigalway.ie

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) 1×107 fibroblasts/kg; (3) 1×107 hMSCs/kg or (4) 2×107 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 5×106 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.

  • ARDS
  • Bacterial Infection

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