The role of adenosine A2A receptor signaling in bronchiolitis obliterans.
BACKGROUND
Binding of adenosine to the anti-inflammatory Gs-coupled adenosine 2A receptor (A(2A)R) inhibits the activity of most inflammatory cells. Extensive preclinical evidence exists for the use of A(2A)R agonists in the prevention of acute ischemia-reperfusion injury. Activation of A(2A)Rs 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(2A)R 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(2A)R signaling in a mouse model of BO. Tracheal transplants were performed using Balb/c donors into wild-type or A(2A)R knockout C57BL/6 recipient mice. Another group of Balb/c transplants into C57BL/6 recipients were also treated with a selective A(2A)R 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(2A)R knockout recipients had increased inflammation and more severe BO development. Recipient wild-type mice treated with a selective A(2A)R 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(2A)R to attenuate inflammatory and immune factors involved in BO development. Synthetic A(2A)R agonists may provide a novel treatment strategy to prevent BO.
Lau
Christine L
CL
Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA. cll2y@virginia.edu
Zhao
Yunge
Y
Kron
Irving L
IL
Stoler
Mark H
MH
Laubach
Victor E
VE
Ailawadi
Gorav
G
Linden
Joel
J
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D007111:Immunity, Cellular / Q000502:physiology*; D007150:Immunohistochemistry; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D014132:Trachea / Q000473:pathology / Q000637:transplantation
D017252:CD3 Complex; D043705:Receptor, Adenosine A2A