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Rationale: Ischemia-reperfusion (IR) injury after lung transplantation, which affects both short-and long-term allograft survival, involves activation of NADPH oxidase 2 (NOX2) and activation of invariant natural killer T (iNKT) cells to produce IL-17. Adenosine A 2A receptor (A 2A R) agonists are known to potently attenuate lung IR injury and IL-17 production. However, mechanisms for iNKT cell activation after IR and A 2A R agonist-mediated protection remain unclear.Objectives: We tested the hypothesis that NOX2 mediates IL-17 production by iNKT cells after IR and that A 2A R agonism prevents IR injury by blocking NOX2 activation in iNKT cells.Methods: An in vivo murine hilar ligation model of IR injury was used, in which left lungs underwent 1 hour of ischemia and 2 hours of reperfusion.Measurements and Main Results: Adoptive transfer of iNKT cells from p47 phox2/2 or NOX2 2/2 mice to Ja18 2/2 (iNKT cell-deficient) mice significantly attenuated lung IR injury and IL-17 production. Treatment with an A 2A R agonist attenuated IR injury and IL-17 production in wild-type (WT) mice and in Ja18 2/2 mice reconstituted with WT, but not A 2A R 2/2, iNKT cells. Furthermore, the A 2A R agonist prevented IL-17 production by murine and human iNKT cells after acute hypoxia-reoxygenation by blocking p47 phox phosphorylation, a critical step for NOX2 activation.Conclusions: NOX2 plays a key role in inducing iNKT cell-mediated IL-17 production and subsequent lung injury after IR. A primary mechanism for A 2A R agonist-mediated protection entails inhibition of NOX2 in iNKT cells. Therefore, agonism of A 2A Rs on iNKT cells may be a novel therapeutic strategy to prevent primary graft dysfunction after lung transplantation.

In this series, aortic root replacement ± hemiarch reconstruction had low mortality. Addition of hemiarch replacement extended perfusion times but not at the expense of safety. Hemiarch reconstruction should be performed when the aortic root aneurysm extends into the distal ascending aorta.

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