title: Pharmacological Reconditioning of Marginal Donor Rat Lungs Using Inhibitors of Peroxynitrite and Poly (ADP-ribose) Polymerase During Ex Vivo Lung Perfusion.
abstract: Donor lungs obtained after prolonged warm ischemia (WI) may be unsuitable for transplantation due to the risk of reperfusion injury, but could be reconditioned using ex-vivo lung perfusion (EVLP). Key processes of reperfusion injury include the formation of reactive oxygen species (ROS)/nitrogen species (RNS) and the activation of poly(adenosine diphosphate-ribose) polymerase (PARP). We explored whether rat lungs obtained after WI could be reconditioned during EVLP using the ROS/RNS scavenger Mn(III)-tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the PARP inhibitor 3-aminobenzamide (3-AB).
  
  
  
  Rat lungs obtained after 3 hours cold ischemia (CI group, control), or 1 hour WI plus 2 hours CI (WI group) were placed in an EVLP circuit for normothermic perfusion for 3 hours. Lungs retrieved after WI were treated or not with 3-AB (1 mg/mL) or MnTBAP (0.3 mg/mL), added to the perfusate. Measurements included physiological variables (lung compliance, vascular resistance, oxygenation capacity), lung weight gain, levels of proteins, lactate dehydrogenase, protein carbonyl (marker of ROS), 3-nitrotyrosine (marker of RNS), poly(adenosine diphosphate-ribose) (PAR, marker of PARP activation) and IL-6, in the bronchoalveolar lavage or the lung tissue, and histology.
  
  
  
  In comparison to the CI group, the lungs from the WI group displayed higher protein carbonyls, 3-nitrotyrosine, PAR, lactate dehydrogenase and proteins in bronchoalveolar lavage, lung weight gain, perivascular edema, as well as reduced static compliance, but similar oxygenation. All these alterations were markedly attenuated by 3-AB and MnTBAP.
  
  
  
  After EVLP, lungs obtained after WI exhibit oxidative stress, PARP activation, and tissue injury, which are suppressed by pharmacological inhibitors of ROS/RNS and PARP.
authors.affiliation: 1 Division of Thoracic Surgery, University Hospital of Lausanne, Lausanne, Switzerland.2 Department of Intensive Care Medicine, University Hospital of Lausanne, Lausanne, Switzerland.3 Department of Anesthesiology, University Hospital of Lausanne, Lausanne, Switzerland.4 University Institute of Pathology, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.forename: Yabo
authors.initials: Y
authors.lastname: Wang
authors.forename: Roumen
authors.initials: R
authors.lastname: Parapanov
authors.forename: Etienne
authors.initials: E
authors.lastname: Abdelnour
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gronchi
authors.forename: Jean Yannis
authors.initials: JY
authors.lastname: Perentes
authors.forename: Lise
authors.initials: L
authors.lastname: Piquilloud
authors.forename: Hans-Beat
authors.initials: HB
authors.lastname: Ris
authors.forename: Igor
authors.initials: I
authors.lastname: Letovanec
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Thorsten
authors.initials: T
authors.lastname: Krueger
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry; D050377:Cold Ischemia; D005112:Extracorporeal Circulation; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000601:surgery*; D008297:Male; D008665:Metalloporphyrins / Q000737:chemistry; D010477:Perfusion / Q000379:methods*; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D001549:Benzamides; D015850:Interleukin-6; D008665:Metalloporphyrins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases