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Original Articles: General Thoracic

The Role of Adenosine A_2A Receptor Signaling in Bronchiolitis Obliterans

^a Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
^b Department of Pathology, University of Virginia Health System, Charlottesville, Virginia
^c Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia

Accepted for publication June 15, 2009.

^_* Address correspondence to Dr Lau, Department of Surgery, PO Box 800679, Charlottesville, VA 22908-0679 (Email: cll2y{at}virginia.edu).

Presented at the Poster Session of the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009

Background: Binding of adenosine to the anti-inflammatory Gs-coupled adenosine 2A receptor (A_2AR) inhibits the activity of most inflammatory cells. Extensive preclinical evidence exists for the use of A_2AR agonists in the prevention of acute ischemia-reperfusion injury. Activation of A_2ARs on lymphocytes and antigen-presenting cells also attenuates the alloimmune response. Because ischemia-reperfusion injury and alloimmunity are risk factors for the development of bronchiolitis obliterans (BO), the objective of this study was to determine the effect of A_2AR signaling on tracheal rejection in a mouse model of BO.

Methods: A non-revascularized heterotopic tracheal model across a total alloantigenic mismatch was used to study A_2AR signaling in a mouse model of BO. Tracheal transplants were performed using Balb/c donors into wild-type or A_2AR knockout C57BL/6 recipient mice. Another group of Balb/c transplants into C57BL/6 recipients were also treated with a selective A_2AR agonist. Tracheas were assessed at 3, 7, 12, 21, and 28 days after transplantation by hematoxylin and eosin staining, immunohistochemical staining, and collagen staining.

Results: Compared with allograft tracheas in wild-type recipients, allografts in A_2AR knockout recipients had increased inflammation and more severe BO development. Recipient wild-type mice treated with a selective A_2AR agonist were significantly protected from lymphocyte infiltration and luminal occlusion, but fibro-obliteration still developed by 28 days after transplantation.

Conclusions: Endogenous adenosine signals through the A_2AR to attenuate inflammatory and immune factors involved in BO development. Synthetic A_2AR agonists may provide a novel treatment strategy to prevent BO.

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