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Victor E. Laubach
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Irving L. Kron
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J Thorac Cardiovasc Surg 2008;135:156-165
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Additive protection against lung ischemia-reperfusion injury by adenosine A2A receptor activation before procurement and during reperfusion

Leo M. Gazoni, MDa,*, Victor E. Laubach, PhDa, Daniel P. Mulloy, BSa, A. Bellizzi, MDb, Eric B. Unger, BSa, Joel Linden, PhDc,1, Peter I. Ellman, MDa, Turner C. Lisle, MDa, Irving L. Kron, MDa,1

a Department of Surgery, University of Virginia, Charlottesville, Va
b Department of Pathology, University of Virginia, Charlottesville, Va
c Medicine/Cardiovascular Research Center, University of Virginia, Charlottesville, Va.

Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5–9, 2007.

Received for publication May 4, 2007; revisions received July 20, 2007; accepted for publication August 1, 2007.

* Address for reprints: Leo M. Gazoni, MD, Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908. (Email: lmg2x{at}virginia.edu).

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°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.

Abbreviations and Acronyms A2AR = A2A receptor; ANOVA = analysis of variance; BAL = bronchoalveolar lavage; ELISA = enzyme-linked immunosorbent assay; IR = ischemia-reperfusion; LIRI = lung ischemia-reperfusion injury; MPO = myeloperoxidase; PA = pulmonary artery; TNF- {alpha} = tumor necrosis factor {alpha}


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