title: The role of the endothelin-1 pathway as a biomarker for donor lung assessment in clinical ex vivo lung perfusion.
abstract: BACKGROUND
  Normothermic ex vivo lung perfusion (EVLP) is a preservation technique that allows reassessment of donor lungs before transplantation. We hypothesized that the endothelin-1 (ET-1) axis would be associated with donor lung performance during EVLP and recipient outcomes after transplantation.
  
  
  METHODS
  ET-1, Big ET-1, endothelin-converting enzyme (ECE), and nitric oxide (NO) metabolites were quantified in the perfusates of donor lungs enrolled in a clinical EVLP trial. Lungs were divided into 3 groups: (I) Control: bilateral transplantation with good early outcomes defined as absence of primary graft dysfunction (PGD) Grade 3 (PGD3) ; (II) PGD3: bilateral lung transplantation with PGD3 any time within 72 hours; and (III) Declined: lungs rejected after EVLP.
  
  
  RESULTS
  There were 25 lungs in Group I, 7 in Group II, and 16 in Group III. At 1 and 4 hours of EVLP, the perfusates of Declined lungs had significantly higher levels of ET-1 (3.1 ± 2.1 vs. 1.8±2.3 pg/ml, p = 0.01; 2.7 ± 2.2 vs. 1.3 ± 1.1 pg/ml, p = 0.007) and Big ET-1 (15.8 ± 14.2 vs. 7.0 ± 6.5 pg/ml, p = 0.001; 31.7 ± 17.4 vs. 19.4 ± 9.5 pg/ml, p = 0.007) compared with Controls. Nitric oxide metabolite concentrations were significantly higher in Declined and PGD3 lungs than in Controls. For cases of donation after cardiac death, PGD3 and Declined lungs had higher ET-1 and Big ET-1 levels at 4 hours of perfusion compared with Controls. At this time point, Big ET-1 had excellent accuracy to distinguish PGD3 (96%) and Declined (92%) from Control lungs.
  
  
  CONCLUSIONS
  In donation after cardiac death lungs, perfusate ET-1 and Big ET-1 are potential predictors of lung function during EVLP and after lung transplantation. They were also associated with non-use of lungs after EVLP and thus could represent useful biomarkers to improve the accuracy of donor lungs selection.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tiago Noguchi
authors.initials: TN
authors.lastname: Machuca
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cypel
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute.
authors.forename: Farshad
authors.initials: F
authors.lastname: Tavasoli
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Yeung
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bonato
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Zamel
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Chun
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute.
authors.forename: Zehong
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address: shaf.keshavjee@uhn.ca.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008168:Lung / Q000378:metabolism*; D016040:Lung Transplantation; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010477:Perfusion / Q000379:methods*; D011237:Predictive Value of Tests; D012131:Respiratory Insufficiency / Q000601:surgery; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D009927:Tissue and Organ Procurement / Q000592:standards*; D066027:Transplant Recipients; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D009569:Nitric Oxide; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes
keywords: ET-1; endothelin axis; ex vivo lung perfusion; primary graft dysfunction; transplant outcomes