title: Anti-inflammatory effects on ischemia/reperfusion-injured lung transplants by the cluster of differentiation 26/dipeptidylpeptidase 4 (CD26/DPP4) inhibitor vildagliptin.
abstract: We showed previously that stromal cell-derived factor 1 (SDF-1) is a substrate of cluster of differentiation 26/dipeptidylpeptidase 4 (CD26/DPP4) and exerts regenerative properties on acute lung ischemia-reperfusion injury on CD26/DPP4 inhibition. Here, we extend our studies to test whether an intermediate recovery of lung transplants from ischemia/reperfusion injury by CD26/DPP4 inhibition can be achieved for up to 14 days.
  
  
  
  Syngeneic mouse lung transplantation (Tx) was performed in C57BL/6 and in CD26-/- mice by applying 18 hours of cold ischemia. Donor lungs were preconditioned with saline or the CD26/DPP4 inhibitor vildagliptin (1 μg/mL [3 μM]). In vitro, the influence of vildagliptin and SDF-1 on the macrophage cell line RAW 264.7 was tested. Transplants were analyzed up to 14 days after Tx for the expression of SDF-1, tumor necrosis factor-α (TNF-α), interleukin-10, intercellular adhesion molecule-1 (ICAM-1), immune cell infiltration, and oxygenation.
  
  
  
  Cold ischemic time of 18 hours with vildagliptin preconditioning elevated lung SDF-1 levels (P = .0011) and increased interleukin-10-producing macrophages (P = .0165) compared with the control. SDF-1 reduced macrophage-derived TNF-α (P = .0248) in vitro. Five hours after Tx, vildagliptin significantly reduced macrophages and neutrophils (P = .0306), decreased ICAM-1 expression (P = .002), and improved transplant oxygenation (P = .0181). Seven days after Tx, grafts were preserved on CD26/DPP4-inhibition: perivascular macrophages (P = .0046) and TNF-α (P = .0013) were reduced as well as T and B cells. ICAM-1 was absent in CD26/DPP4-inhibited grafts at all time points.
  
  
  
  This study proves an intermediate improvement of ischemia/reperfusion-injured lung transplants by the CD26/DPP4-inhibitor vildagliptin up to 14 days. Enhanced levels of SDF-1 induced an anti-inflammatory effect on a cellular and protein level, and render CD26/DPP4 inhibition preconditioning effective for the protection from lung ischemia/reperfusion injury.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Janker
authors.affiliation: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.affiliation: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Lesley
authors.initials: L
authors.lastname: Baerts
authors.affiliation: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Vliegen
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ilhan
authors.initials: I
authors.lastname: Inci
authors.affiliation: Institute for Environmental Medicine and Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: Shampa
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. Electronic address: wolfgang.jungraithmayr@usz.ch.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D016040:Lung Transplantation / Q000009:adverse effects*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000077597:Vildagliptin / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin
keywords: CD26/DPP4; ICAM-1; IL-10; SDF-1; macrophages; mouse lung transplantation