Apyrase treatment prevents ischemia-reperfusion injury in rat lung isografts

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)752-759
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume138
Issue number3
DOIs
Publication statusPublished - Sep 2009
Externally publishedYes

Fingerprint

Apyrase
Isografts
Reperfusion Injury
Adenosine Triphosphate
Lung
Inflammation
Reperfusion
Transplants
Lung Transplantation
Sodium Chloride
Adenosine Diphosphate
Nucleotides
Endothelial Cells
Isogeneic Transplantation
Therapeutics
Cold Ischemia
Lung Injury
Pulmonary Edema
Peroxidase
Blood Vessels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Apyrase treatment prevents ischemia-reperfusion injury in rat lung isografts. / Sugimoto, Seiichiro; Lin, Xue; Lai, Jiaming; Okazaki, Mikio; Das, Nitin A.; Li, Wenjun; Krupnick, Alexander S.; Chen, Ridong; Jeong, Soon Seog; Patterson, G. A.; Kreisel, Daniel; Gelman, Andrew E.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 138, No. 3, 09.2009, p. 752-759.

Research output: Contribution to journalArticle

Sugimoto, S, Lin, X, Lai, J, Okazaki, M, Das, NA, Li, W, Krupnick, AS, Chen, R, Jeong, SS, Patterson, GA, Kreisel, D & Gelman, AE 2009, 'Apyrase treatment prevents ischemia-reperfusion injury in rat lung isografts', Journal of Thoracic and Cardiovascular Surgery, vol. 138, no. 3, pp. 752-759. https://doi.org/10.1016/j.jtcvs.2009.04.049
Sugimoto, Seiichiro ; Lin, Xue ; Lai, Jiaming ; Okazaki, Mikio ; Das, Nitin A. ; Li, Wenjun ; Krupnick, Alexander S. ; Chen, Ridong ; Jeong, Soon Seog ; Patterson, G. A. ; Kreisel, Daniel ; Gelman, Andrew E. / Apyrase treatment prevents ischemia-reperfusion injury in rat lung isografts. In: Journal of Thoracic and Cardiovascular Surgery. 2009 ; Vol. 138, No. 3. pp. 752-759.
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AU - Lin, Xue

AU - Lai, Jiaming

AU - Okazaki, Mikio

AU - Das, Nitin A.

AU - Li, Wenjun

AU - Krupnick, Alexander S.

AU - Chen, Ridong

AU - Jeong, Soon Seog

AU - Patterson, G. A.

AU - Kreisel, Daniel

AU - Gelman, Andrew E.

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N2 - 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.

AB - 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.

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