Regadenoson Reduces Soluble Receptor for Advanced Glycation End-Products in Lung Recipients.

BACKGROUND: The selective adenosine A2A receptor (A2AR) agonist Regadenoson reduces inflammation due to lung ischemia-reperfusion injury (IRI). The objective of this study was to investigate molecular and cellular mechanisms by which regadenoson reduces IRI in lung transplant recipients.

METHODS: Fourteen human lung transplant recipients were infused for 12 hours with regadenoson and seven more served as untreated controls. Plasma levels of high mobility group box 1 and its soluble receptor for advanced glycation end-products (sRAGE) were measured by Luminex. Matrix metalloproteinass-2 and -9 (MMP-2 and MMP-9) were measured by gelatin zymography. Tissue inhibitor of metalloproteinase-1 was measured by mass spectroscopy. A2AR expression on leukocytes was analyzed by flow cytometry. MMP-9-mediated cleavage of RAGE was evaluated using cultured macrophages in vitro.

RESULTS: Regadenoson treatment during lung transplantation significantly reduced levels of MMP-9 (p<0.05), but not MMP-2, and elevated levels of Tissue Inhibitor of Metalloproteinase-1 (p<0.05), an endogenous selective inhibitor of MMP-9. Regadenoson infusion significantly reduced plasma levels of sRAGE (P<0.05) during lung reperfusion when compared with control subjects. A2AR expression was highest on iNKT cells and higher on monocytes than other circulating immune cells (p<0.05). The shedding of RAGE from cultured monocytes/macrophages was increased by MMP-9 stimulation and reduced by an MMP inhibitor or by A2AR agonists, regadenoson or ATL146e.

CONCLUSIONS: In vivo and in vitro studies suggest that A2AR activation reduces sRAGE in part by inhibiting MMP-9 production by monocytes/macrophages. These results suggest a novel molecular mechanism by which A2AR agonists reduces primary graft dysfunction.