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J Thorac Cardiovasc Surg 2009;138:752-759
© 2009 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Apyrase treatment prevents ischemia–reperfusion injury in rat lung isografts

Seiichiro Sugimoto, MD, PhDa, Xue Lin, MDa, Jiaming Lai, MDa, Mikio Okazaki, MD, PhDa, Nitin A. Das, MDa, Wenjun Li, MDa, Alexander S. Krupnick, MDa, Ridong Chen, PhDb, Soon Seog Jeong, PhDb, G.A. Patterson, MDa, Daniel Kreisel, MD, PhDa, Andrew E. Gelman, PhDa,*

a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, Mo
b APT Therapeutics Inc, St Louis, Mo

Received for publication November 7, 2008; revisions received March 27, 2009; accepted for publication April 23, 2009.

* Address for reprints: Andrew E. Gelman, PhD, Assistant Professor of Surgery, Pathology & Immunology, Campus Box 8234, 660 South Euclid Avenue, Washington University in St Louis, St Louis, MO 63110-1013. (Email: gelmana{at}wudosis.wustl.edu).

Objective: Endothelial cells express the ectoenzyme ectonucleoside adenosine triphosphate diphosphohydrolase, an apyrase that inhibits vascular inflammation by catalyzing the hydrolysis of adenosine triphosphate and adenosine diphosphate. However, ectonucleoside adenosine triphosphate diphosphohydrolase expression is rapidly lost following oxidative stress, leading to the potential for adenosine triphosphate and related purigenic nucleotides to exacerbate acute solid organ inflammation and injury. We asked if administration of a soluble recombinant apyrase APT102 attenuates lung graft injury in a cold ischemia reperfusion model of rat syngeneic orthotopic lung transplantation.

Methods: Male Fisher 344 donor lungs were cold preserved in a low-potassium dextrose solution in the presence or absence of APT102 for 18 hours prior to transplantation into syngeneic male Fisher 344 recipients. Seven minutes after reperfusion, lung transplant recipients received either a bolus of APT102 or vehicle (saline solution). Four hours after reperfusion, APT102- and saline solution–treated groups were evaluated for lung graft function and inflammation.

Results: APT102 significantly reduced lung graft extracellular pools of adenosine triphosphate and adenosine diphosphate, improved oxygenation, and protected against pulmonary edema. Apyrase treatment was associated with attenuated neutrophil graft sequestration and less evidence of tissue inflammation as assessed by myeloperoxidase activity, expression of proinflammatory mediators, and numbers of apoptotic endothelial cells.

Conclusions: Administration of a soluble recombinant apyrase promotes lung function and limits the tissue damage induced by prolonged cold storage, indicating that extracellular purigenic nucleotides play a key role in promoting ischemia–reperfusion injury following lung transplantation.

Abbreviations and Acronyms ADP = adenosine diphosphate; ATP = adenosine triphosphate; BAL = bronchoalveolar lavage; CD39 = ectonucleoside triphosphate diphosphohydrolase-1; EBD = Evans blue dye; EC = endothelial cell; ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G; IL-1β = inteleukin-1β; IRI = ischemia–reperfusion injury; MIP-2 = macrophage inflammatory protein-2; MPO = myeloperoxidase; PBS = phosphate-buffered saline; TNF-{alpha} = tumor necrosis factor-{alpha}; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling






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