title: Adenosine A3 receptor activation attenuates lung ischemia-reperfusion injury.
abstract: BACKGROUND
  Severe ischemia-reperfusion (IR) injury leads to primary graft dysfunction after lung transplantation. Adenosine receptors modulate inflammation after IR, and the adenosine A3 receptor (A3R) is expressed in lung tissue and inflammatory cells. This study tests the hypothesis that A3R agonism attenuates lung IR injury by a neutrophil-dependent mechanism.
  
  
  METHODS
  Wild-type and A3R knockout (A3R-/-) mice underwent 1-hour left lung ischemia followed by 2-hours reperfusion (IR). A selective A3R agonist, Cl-IB-MECA, was administered (100 μg/kg intravenously) 5 minutes prior to ischemia. Study groups included sham, IR, and IR+Cl-IB-MECA (n = 6/group). Lung injury was assessed by measuring lung function, pulmonary edema, histopathology, and proinflammatory cytokines, and myeloperoxidase levels in bronchoalveolar lavage fluid. Parallel in vitro experiments were performed to evaluate neutrophil chemotaxis, and neutrophil activation was measured after exposure to acute hypoxia and reoxygenation.
  
  
  RESULTS
  Treatment of wild-type mice with Cl-IB-MECA significantly improved lung function and decreased edema, cytokine expression, and neutrophil infiltration after IR. The Cl-IB-MECA had no effects in A3R-/- mice; Cl-IB-MECA significantly decreased activation of wild-type, but not A3R-/-, neutrophils after acute hypoxia and reoxygenation and inhibited chemotaxis of wild-type neutrophils.
  
  
  CONCLUSIONS
  Exogenous activation of A3R by Cl-IB-MECA attenuates lung dysfunction, inflammation, and neutrophil infiltration after IR in wild-type but not A3R-/- mice. Results with isolated neutrophils suggest that the protective effects of Cl-IB-MECA are due, in part, to the prevention of neutrophil activation and chemotaxis. The use of A3R agonists may be a novel therapeutic strategy to prevent lung IR injury and primary graft dysfunction after transplantation.
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Mulloy
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Lucas G
authors.initials: LG
authors.lastname: Fernandez
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058909:Adenosine A3 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D002634:Chemotaxis, Leukocyte; D008168:Lung / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration / Q000187:drug effects; D043684:Receptor, Adenosine A3 / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D058909:Adenosine A3 Receptor Agonists; D043684:Receptor, Adenosine A3; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide
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