Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia-reperfusion injury.
OBJECTIVE
Ischemia-reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro- and anti-inflammatory roles in ischemia-reperfusion injury. This study tests the hypothesis that the adenosine A(2B) receptor exacerbates the proinflammatory response to lung ischemia-reperfusion injury.


METHODS
An in vivo left lung hilar clamp model of ischemia-reperfusion was used in wild-type C57BL6 and adenosine A(2B) receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A(2B) receptor knockout mice. Mice underwent sham surgery or lung ischemia-reperfusion (1 hour ischemia and 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring proinflammatory cytokine levels in bronchoalveolar lavage fluid, and neutrophil infiltration was assessed via myeloperoxidase levels in lung tissue.


RESULTS
Compared with wild-type mice, lungs of adenosine A(2B) receptor knockout mice were significantly protected after ischemia-reperfusion, as evidenced by significantly reduced pulmonary artery pressure, increased lung compliance, decreased myeloperoxidase, and reduced proinflammatory cytokine levels (tumor necrosis factor-α; interleukin-6; keratinocyte chemoattractant; regulated on activation, normal T-cell expressed and secreted; and monocyte chemotactic protein-1). Adenosine A(2B) receptor knockout → adenosine A(2B) receptor knockout (donor → recipient) and wild-type → adenosine A(2B) receptor knockout, but not adenosine A(2B) receptor knockout → wild-type, chimeras showed significantly improved lung function after ischemia-reperfusion.


CONCLUSIONS
These results suggest that the adenosine A(2B) receptor plays an important role in mediating lung inflammation after ischemia-reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A(2B) receptor seem to be derived by adenosine A(2B) receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A(2B) receptor may provide a therapeutic target for prevention of ischemia-reperfusion-related graft dysfunction in lung transplant recipients.
Anvari
Farshad
F
Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
Sharma
Ashish K
AK
Fernandez
Lucas G
LG
Hranjec
Tjasa
T
Ravid
Katya
K
Kron
Irving L
IL
Laubach
Victor E
VE
D000818:Animals; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D012129:Respiratory Function Tests; D018183:Transplantation Chimera
D016207:Cytokines; D018836:Inflammation Mediators; D043704:Receptor, Adenosine A2B