Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia–reperfusion injury
Received 28 April 2010; received in revised form 14 June 2010; accepted 28 June 2010. published online 26 July 2010. Corrected Proof
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 A2B 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 A2B receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A2B 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 A2B 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 A2B receptor knockout→adenosine A2B receptor knockout (donor→recipient) and wild-type→ adenosine A2B receptor knockout, but not adenosine A2B receptor knockout→wild-type, chimeras showed significantly improved lung function after ischemia–reperfusion.
Conclusion
These results suggest that the adenosine A2B receptor plays an important role in mediating lung inflammation after ischemia–reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A2B receptor seem to be derived by adenosine A2B receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A2B receptor may provide a therapeutic target for prevention of ischemia–reperfusion-related graft dysfunction in lung transplant recipients.
aDepartment of Surgery, University of Virginia Health System, Charlottesville, Va
bDepartments of Biochemistry and Medicine, Boston University School of Medicine, Boston, Mass
Address for reprints: Victor E. Laubach, PhD, Department of Surgery, University of Virginia Health System, P.O. Box 801359, Charlottesville, VA 22908.
This study was funded by National Institutes of Health/National Heart, Lung, and Blood Institute grants R01 HL092953 (to V.E.L.) and T32 HL007849 (to I.L.K.).
ABSTRACT