Adenosine A2A receptor activation on CD4+ T lymphocytes and neutrophils attenuates lung ischemia-reperfusion injury.
OBJECTIVE
Adenosine A(2A) receptor activation potently attenuates lung ischemia-reperfusion injury. This study tests the hypothesis that adenosine A(2A) receptor activation attenuates ischemia-reperfusion injury by inhibiting CD4+ T cell activation and subsequent neutrophil infiltration.


METHODS
An in vivo model of lung ischemia-reperfusion injury was used. C57BL/6 mice were assigned to either sham group (left thoracotomy) or 7 study groups that underwent ischemia-reperfusion (1 hour of left hilar occlusion plus 2 hours of reperfusion). ATL313, a selective adenosine A(2A) receptor agonist, was administered 5 minutes before reperfusion with or without antibody depletion of neutrophils or CD4+ T cells. After reperfusion, the following was measured: pulmonary function using an isolated, buffer-perfused lung system, T cell infiltration by immunohistochemistry, myeloperoxidase and proinflammatory cytokine/chemokine levels in bronchoalveolar lavage fluid, lung wet/dry weight, and microvascular permeability.


RESULTS
ATL313 significantly improved pulmonary function and reduced edema and microvascular permeability after ischemia-reperfusion compared with control. Immunohistochemistry and myeloperoxidase content demonstrated significantly reduced infiltration of neutrophils and CD4+ T cells after ischemia-reperfusion in ATL313-treated mice. Although CD4+ T cell-depleted and neutrophil-depleted mice displayed significantly reduced lung injury, no additional protection occurred when ATL313 was administered to these mice. Expression of tumor necrosis factor-alpha, interleukin 17, KC, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and RANTES were significantly reduced in neutrophil- and CD4+ T cell-depleted mice and reduced further by ATL313 only in neutrophil-depleted mice.


CONCLUSIONS
These results demonstrate that CD4+ T cells play a key role in mediating lung inflammation after ischemia-reperfusion. ATL313 likely exerts its protective effect largely through activation of adenosine A(2A) receptors on CD4+ T cells and neutrophils.
Sharma
Ashish K
AK
Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
Laubach
Victor E
VE
Ramos
Susan I
SI
Zhao
Yunge
Y
Stukenborg
George
G
Linden
Joel
J
Kron
Irving L
IL
Yang
Zequan
Z
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D007150:Immunohistochemistry; D008171:Lung Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D012129:Respiratory Function Tests
C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D018925:Chemokines; D016207:Cytokines; D010880:Piperidines