title: Therapeutic efficacy of human mesenchymal stromal cells in the repair of established ventilator-induced lung injury in the rat.
abstract: BACKGROUND
  Rodent mesenchymal stem/stromal cells (MSCs) enhance repair after ventilator-induced lung injury (VILI). We wished to determine the therapeutic potential of human MSCs (hMSCs) in repairing the rodent lung.
  
  
  METHODS
  In series 1, anesthetized rats underwent VILI (series 1A, n = 8 to 9 per group) or protective ventilation (series 1B, n = 4 per group). After VILI, they were randomized to intravenous administration of (1) vehicle (phosphate-buffered saline); (2) fibroblasts (1 × 10 cells/kg); or (3) human MSCs (1 × 10 cells/kg) and the effect on restoration of lung function and structure assessed. In series 2, the efficacy of hMSC doses of 1, 2, 5, and 10 million/kg was examined (n = 8 per group). Series 3 compared the efficacy of both intratracheal and intraperitoneal hMSC administration to intravascular delivery (n = 5-10 per group). Series 4 examined the efficacy of delayed hMSC administration (n = 8 per group).
  
  
  RESULTS
  Human MSC's enhanced lung repair, restoring oxygenation (131 ± 19 vs. 103 ± 11 vs. 95 ± 11 mmHg, P = 0.004) compared to vehicle or fibroblast therapy, respectively. hMSCs improved lung compliance, reducing alveolar edema, and restoring lung architecture. hMSCs attenuated lung inflammation, decreasing alveolar cellular infiltration, and decreasing cytokine-induced neutrophil chemoattractant-1 and interleukin-6 while increasing keratinocyte growth factor concentrations. The lowest effective hMSC dose was 2 × 10 hMSC/kg. Intraperitoneal hMSC delivery was less effective than intratracheal or intravenous hMSC. hMSCs enhanced lung repair when administered at later time points after VILI.
  
  
  CONCLUSIONS
  hMSC therapy demonstrates therapeutic potential in enhancing recovery after VILI.
authors.affiliation: From the Regenerative Medicine Institute, National University of Ireland, Galway, Ireland (M.H., C.M., J.D., F.B., T.O., D.O., G.F.C., J.G.L.); Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland (M.H., C.M., J.D., D.O.); Orbsen Therapeutics Ltd, National University of Ireland, Galway, Ireland (S.E; and Department of Anesthesia, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada (G.F.C., J.G.L.).
authors.forename: Mairead
authors.initials: M
authors.lastname: Hayes
authors.forename: Claire
authors.initials: C
authors.lastname: Masterson
authors.forename: James
authors.initials: J
authors.lastname: Devaney
authors.forename: Frank
authors.initials: F
authors.lastname: Barry
authors.forename: Steve
authors.initials: S
authors.lastname: Elliman
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Curley
authors.forename: John G
authors.initials: JG
authors.lastname: Laffey
mesh_terms: D000818:Animals; D005347:Fibroblasts; D006801:Humans; D008168:Lung / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D055397:Ventilator-Induced Lung Injury / Q000473:pathology / Q000628:therapy*