Journal
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Volume 135, Issue 1, Pages 156-165Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jtcvs.2007.08.041
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Funding
- NHLBI NIH HHS [R01 HL 056093, 5 T32 HL007849] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL056093, T32HL007849] Funding Source: NIH RePORTER
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Objective: Adenosine A(2A) 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 A(2A) 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 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 A(2A) 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 A(2A) 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 A(2A) receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A(2A) receptor activation.
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