Format

Send to

Choose Destination
J Heart Lung Transplant. 2015 Feb;34(2):247-53. doi: 10.1016/j.healun.2014.09.034. Epub 2014 Oct 2.

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

Author information

1
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Thoracic Surgery, Sapienza University, Rome, Italy.
2
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
3
Departments of Anesthesia.
4
Medicine.
5
Department of Thoracic Surgery, Sapienza University, Rome, Italy.
6
APT Therapeutics Inc, St. Louis, Missouri.
7
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri.
8
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.

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.

KEYWORDS:

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

PMID:
25455749
PMCID:
PMC4329251
DOI:
10.1016/j.healun.2014.09.034
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center