The Role of Adenosine A2A Receptor Signaling in Bronchiolitis Obliterans

Christine L. Lau, Yunge Zhao, Irving L. Kron, Mark H. Stoler, Victor E. Laubach, Gorav Ailawadi, Joel Linden

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Background: Binding of adenosine to the anti-inflammatory Gs-coupled adenosine 2A receptor (A2AR) inhibits the activity of most inflammatory cells. Extensive preclinical evidence exists for the use of A2AR agonists in the prevention of acute ischemia-reperfusion injury. Activation of A2ARs 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 A2AR 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 A2AR signaling in a mouse model of BO. Tracheal transplants were performed using Balb/c donors into wild-type or A2AR knockout C57BL/6 recipient mice. Another group of Balb/c transplants into C57BL/6 recipients were also treated with a selective A2AR 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 A2AR knockout recipients had increased inflammation and more severe BO development. Recipient wild-type mice treated with a selective A2AR 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 A2AR to attenuate inflammatory and immune factors involved in BO development. Synthetic A2AR agonists may provide a novel treatment strategy to prevent BO.

Original languageEnglish (US)
Pages (from-to)1071-1078
Number of pages8
JournalAnnals of Thoracic Surgery
Volume88
Issue number4
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

ASJC Scopus subject areas

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

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    Lau, C. L., Zhao, Y., Kron, I. L., Stoler, M. H., Laubach, V. E., Ailawadi, G., & Linden, J. (2009). The Role of Adenosine A2A Receptor Signaling in Bronchiolitis Obliterans. Annals of Thoracic Surgery, 88(4), 1071-1078. https://doi.org/10.1016/j.athoracsur.2009.06.032