title: Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation.
abstract: Ex vivo lung perfusion (EVLP) presents a unique therapeutic opportunity to administer mesenchymal stromal cells (MSCs) to lung grafts before transplantation. We sought to determine the optimal route and dose of viable human umbilical cord-derived MSCs to be delivered into ex vivo-perfused damaged swine lungs, and to measure their effect on concentration of growth factors and inflammatory mediators.
  
  
  
  Pig lungs were conventionally retrieved, cold preserved for 18 hours, and perfused normothermically ex vivo for 12 hours. Physiologic data were recorded. No cells were administered to a control group of animals (n = 5). To examine the routes of administration, lungs were administered 50 × 106MSCs endobronchially (n = 3) or via the pulmonary artery (n = 3). To determine the doses, a dose-escalation study was performed wherein lungs were administered 50 × 106(n = 3), 150 × 106(n = 5) and 300 × 106(n = 3) MSCs via the pulmonary artery. Concentrations of human growth factors and pig cytokines were measured in lung biopsies and perfusate.
  
  
  
  Intravascular administration of 50 × 106MSCs was associated with significant and sustained retention of MSCs in lung parenchyma, whereas intrabronchial administration was not. Intravascular administration of 150 × 106MSCs was the optimal tolerated dose and was associated with increased concentrations of human vascular endothelial growth factor (VEGF) in lung biopsies and decreased concentrations of pig interleukin-8 (IL-8) in the perfusate during 12 hours of EVLP.
  
  
  
  Intravascular delivery of 150 × 106MSCs showed preferred outcome compared with intrabronchial delivery to damaged lungs perfused ex vivo. The method was well tolerated and associated with an increased concentration of human VEGF in the lung tissue and a decreased concentration of pig IL-8 in the perfusate.
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mordant
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakajima
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Kalaf
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Ilker
authors.initials: I
authors.lastname: Iskender
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Lucas
authors.initials: L
authors.lastname: Maahs
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Paula
authors.initials: P
authors.lastname: Behrens
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Rafael
authors.initials: R
authors.lastname: Coutinho
authors.affiliation: Tissue Regeneration Therapeutics, Inc., Toronto, Ontario, Canada.
authors.forename: Rohin K
authors.initials: RK
authors.lastname: Iyer
authors.affiliation: Tissue Regeneration Therapeutics, Inc., Toronto, Ontario, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cypel
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.affiliation: Toronto Lung Transplant Program, Latner Thoracic Surgery Laboratories, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada. Electronic address: shaf.keshavjee@uhn.ca.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000818:Animals; D016209:Interleukin-8; D008168:Lung; D016040:Lung Transplantation; D059630:Mesenchymal Stem Cells; D010477:Perfusion; D013552:Swine; D042461:Vascular Endothelial Growth Factor A
chemical_list: D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A
keywords: cell therapy; ex vivo lung perfusion; lung preservation; lung transplantation; mesenchymal stromal cells