Additive protection against lung ischemia-reperfusion injury by adenosine A2A receptor activation before procurement and during reperfusion.
OBJECTIVE
Adenosine A2A receptor activation during reperfusion improves lung ischemia-reperfusion injury. In this study we sought to determine whether pretreatment of rabbits with a potent and selective adenosine A2A receptor agonist, ATL-313, before transplantation or whether adding ATL-313 to the preservation solution results in equivalent or additional protection compared with ATL-313 added during reperfusion.


METHODS
An isolated, ventilated, ex vivo blood-perfused rabbit lung model was used. All groups underwent 2 hours of reperfusion after 18 hours of cold ischemia (4 degrees C). ATL-313 was administered 1 hour before ischemia intravenously, with the preservation solution, and/or during reperfusion.


RESULTS
Both pretreatment of donor animals with ATL-313 or adding ATL-313 just during reperfusion improved pulmonary function, but significantly greater improvement was observed when pretreatment and treatment during reperfusion were combined (all P < .05). Myeloperoxidase levels, bronchoalveolar lavage tumor necrosis factor alpha levels, and pulmonary edema were all maximally decreased in the combined treatment group. The administration of an equimolar amount of the potent and highly selective adenosine 2A receptor antagonist, ZM 241385, along with ATL-313, resulted in the loss of protection conferred by ATL-313.


CONCLUSIONS
Adenosine A2A receptor activation with ATL-313 results in the greatest protection against lung ischemia-reperfusion injury when given before ischemia and during reperfusion. Improved pulmonary function observed with adenosine A2A receptor activation was correlated with decreased bronchoalveolar lavage tumor necrosis factor alpha and decreased lung myeloperoxidase. The loss of protection observed with the concurrent administration of the adenosine A2A receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A2A receptor activation.
Gazoni
Leo M
LM
Department of Surgery, University of Virginia, Charlottesville 22908, USA. lmg2x@virginia.edu
Laubach
Victor E
VE
Mulloy
Daniel P
DP
Bellizzi
A
A
Unger
Eric B
EB
Linden
Joel
J
Ellman
Peter I
PI
Lisle
Turner C
TC
Kron
Irving L
IL
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D066298:In Vitro Techniques; D008171:Lung Diseases / Q000517:prevention & control*; D016040:Lung Transplantation; D008297:Male; D023421:Models, Animal; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D020858:Tissue and Organ Harvesting
C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D000893:Anti-Inflammatory Agents; D010880:Piperidines; D043705:Receptor, Adenosine A2A