title: Human recombinant apyrase therapy protects against canine pulmonary ischemia-reperfusion injury.
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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Thoracic Surgery, Sapienza University, Rome, Italy.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ibrahim
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Xingan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Anesthesia.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Puyo
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Montecalvo
authors.affiliation: Medicine.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Medicine.
authors.forename: Ramsey R
authors.initials: RR
authors.lastname: Hachem
authors.affiliation: Department of Thoracic Surgery, Sapienza University, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Andreetti
authors.affiliation: Department of Thoracic Surgery, Sapienza University, Rome, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Menna
authors.affiliation: APT Therapeutics Inc, St. Louis, Missouri.
authors.forename: Ridong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krupnick
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.affiliation: Department of Thoracic Surgery, Sapienza University, Rome, Italy.
authors.forename: Erino A
authors.initials: EA
authors.lastname: Rendina
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Thoracic Surgery, Sapienza University, Rome, Italy; Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri. Electronic address: gelmana@wudosis.wustl.edu.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
mesh_terms: D000818:Animals; D001081:Apyrase / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D008168:Lung / Q000098:blood supply*; D008171:Lung Diseases / Q000517:prevention & control*; D016040:Lung Transplantation; D055031:Primary Graft Dysfunction; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D011994:Recombinant Proteins; D001081:Apyrase
keywords: canine model; extracellular adenosine triphosphate; human lung transplantation; human recombinant apyrase therapy; ischemia-reperfusion injury; primary lung graft dysfunction; pulmonary