Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury.
OBJECTIVE
Adenosine and the activation of specific adenosine receptors are implicated in the attenuation of inflammation and organ ischemia-reperfusion injury. We hypothesized that activation of A(1), A(2A), or A(3) adenosine receptors would provide protection against lung ischemia-reperfusion injury.


METHODS
With the use of an isolated, ventilated, blood-perfused rabbit lung model, lungs underwent 18 hours of cold ischemia followed by 2 hours of reperfusion. Lungs were administered vehicle, adenosine, or selective A(1), A(2A), or A(3) receptor agonists (CCPA, ATL-313, or IB-MECA, respectively) alone or with their respective antagonists (DPCPX, ZM241385, or MRS1191) during reperfusion.


RESULTS
Compared with the vehicle-treated control group, treatment with A(1), A(2A), or A(3) agonists significantly improved function (increased lung compliance and oxygenation and decreased pulmonary artery pressure), decreased neutrophil infiltration by myeloperoxidase activity, decreased edema, and reduced tumor necrosis factor-alpha production. Adenosine treatment was also protective, but not to the level of the agonists. When each agonist was paired with its respective antagonist, all protective effects were blocked. The A(2A) agonist reduced pulmonary artery pressure and myeloperoxidase activity and increased oxygenation to a greater degree than the A(1) or A(3) agonists.


CONCLUSIONS
Selective activation of A(1), A(2A), or A(3) adenosine receptors provides significant protection against lung ischemia-reperfusion injury. The decreased elaboration of the potent proinflammatory cytokine tumor necrosis factor-alpha and decreased neutrophil sequestration likely contribute to the overall improvement in pulmonary function. These results provide evidence for the therapeutic potential of specific adenosine receptor agonists in lung transplant recipients.
Gazoni
Leo M
LM
Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
Walters
Dustin M
DM
Unger
Eric B
EB
Linden
Joel
J
Kron
Irving L
IL
Laubach
Victor E
VE
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D010477:Perfusion; D009195:Peroxidase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011654:Pulmonary Edema / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D011817:Rabbits; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C510376:ATL 313; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D010880:Piperidines; D020011:Protective Agents; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D014409:Tumor Necrosis Factor-alpha; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; C048599:N(6)-cyclopentyladenosine; D009195:Peroxidase; D000241:Adenosine
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