TY - JOUR
T1 - The Role of Adenosine A2A Receptor Signaling in Bronchiolitis Obliterans
AU - Lau, Christine L.
AU - Zhao, Yunge
AU - Kron, Irving L.
AU - Stoler, Mark H.
AU - Laubach, Victor E.
AU - Ailawadi, Gorav
AU - Linden, Joel
N1 - Funding Information:
We are grateful to the Adenosine Therapeutics Group of PGx Health for their gift of ATL 313. Dr Linden received support from National Institutes of Health grant R01-HL37942. Dr Lau is supported by the National Heart, Lung, and Blood Institute (1K08HL094704–01) and by the Cardiovascular Research Center (CVRC) Partner's Grant. Dr Lau is the American Association of Thoracic Surgery John W. Kirklin Research Fellow.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/10
Y1 - 2009/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70249122395&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70249122395&partnerID=8YFLogxK
U2 - 10.1016/j.athoracsur.2009.06.032
DO - 10.1016/j.athoracsur.2009.06.032
M3 - Article
C2 - 19766783
AN - SCOPUS:70249122395
VL - 88
SP - 1071
EP - 1078
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
SN - 0003-4975
IS - 4
ER -