Human recombinant apyrase therapy protects against canine pulmonary ischemia-reperfusion injury

Mohsen Ibrahim, Xingan Wang, Carlos A. Puyo, Alessandro Montecalvo, Howard J. Huang, Ramsey R. Hachem, Claudio Andreetti, Cecilia Menna, Ridong Chen, Alexander S. Krupnick, Daniel Kreisel, Erino A. Rendina, Andrew E. Gelman

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of these data are from inbred rodent models, indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung graft dysfunction (PGD). Methods Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, n = 7) or saline vehicle (n = 7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity, and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels. Results APT102-treated dogs had progressively better lung function and less pulmonary edema during the 3-hour reperfusion period compared with vehicle-treated controls. Protection from IRI was observed, with lower BALF eATP levels, fewer airway leukocytes, and blunted inflammatory mediator expression. Human lung recipients with moderate to severe PGD had significantly higher eATP levels compared with recipients without this injury. Conclusions Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI.

Original languageEnglish (US)
Pages (from-to)247-253
Number of pages7
JournalJournal of Heart and Lung Transplantation
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2015

Keywords

  • canine model
  • extracellular adenosine triphosphate
  • human lung transplantation
  • ischemia-reperfusion injury
  • primary lung graft dysfunction human recombinant apyrase therapy
  • pulmonary

ASJC Scopus subject areas

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

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