title: Pretreatment strategy with adenosine A2A receptor agonist attenuates reperfusion injury in a preclinical porcine lung transplantation model.
abstract: OBJECTIVE
  Adenosine A(2A) receptor activation after lung transplantation attenuates ischemia-reperfusion injury by reducing inflammation. However, the effect of adenosine A(2A) receptor activation in donor lungs before transplant remains ill defined. This study compares the efficacy of 3 different treatment strategies for adenosine A(2A) receptor agonist in a clinically relevant porcine lung transplantation model.
  
  
  METHODS
  Mature porcine lungs underwent 6 hours of cold ischemia before allotransplantation and 4 hours of reperfusion. Five groups (n = 6/group) were evaluated on the basis of treatment with ATL-1223, a selective adenosine A(2A) receptor agonist: thoracotomy alone (sham), transplant alone (ischemia-reperfusion), donor pretreatment via ATL-1223 bolus (ATL-D), recipient treatment via ATL-1223 infusion (ATL-R), and a combination of both ATL-1223 treatments (ATL-D/R). Lung function and injury were compared.
  
  
  RESULTS
  Blood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus ischemia-reperfusion (392.0 ± 52.5, 428.9 ± 25.5, and 509.4 ± 25.1 vs 77.2 ± 17.0 mm Hg, respectively, P < .001). ATL-1223-treated groups had lower pulmonary artery pressures (ATL-D = 30.5 ± 1.8, ATL-R = 30.2 ± 3.3, and ATL-D/R = 29.3 ± 4.5 vs IR = 45.2 ± 2.1 mm Hg, P < .001) and lower mean airway pressures versus ischemia-reperfusion (ATL-D = 9.1 ± 0.8, ATL-R = 9.1 ± 2.6, and ATL-D/R = 9.6 ± 1.3 vs IR = 21.1 mm Hg, P < .001). Likewise, ATL-1223-treated groups had significantly lower lung wet/dry weight, proinflammatory cytokine expression, and lung injury scores by histology compared with ischemia-reperfusion. All parameters of lung function and injury in ATL-1223-treated groups were similar to sham (all P > .05).
  
  
  CONCLUSIONS
  Pretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against ischemia-reperfusion injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A(2A)R agonists for use in human clinical trials for lung transplantation.
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: LaPar
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
authors.forename: Abbas
authors.initials: A
authors.lastname: Emaminia
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Crosby
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Hajzus
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Heather M
authors.initials: HM
authors.lastname: Sumner
authors.forename: David V
authors.initials: DV
authors.lastname: Webb
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure; D050377:Cold Ischemia; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D010100:Oxygen / Q000097:blood; D011651:Pulmonary Artery / Q000503:physiopathology; D011654:Pulmonary Edema / Q000209:etiology / Q000517:prevention & control; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012129:Respiratory Function Tests; D034421:Sus scrofa; D013997:Time Factors
chemical_list: D058908:Adenosine A2 Receptor Agonists; D016207:Cytokines; D018836:Inflammation Mediators; D043705:Receptor, Adenosine A2A; D010100:Oxygen