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Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver. Proc Natl Acad Sci U S A 2013 Jul 16;110(29):12012-7



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Ischemia and reperfusion significantly contributes to the morbidity and mortality of liver surgery and transplantation. Based on studies showing a critical role for adenosine signaling in mediating tissue adaptation during hypoxia, we hypothesized that signaling events through adenosine receptors (ADORA1, ADORA2A, ADORA2B, or ADORA3) attenuates hepatic ischemia and reperfusion injury. Initial screening studies of human liver biopsies obtained during hepatic transplantation demonstrated a selective and robust induction of ADORA2B transcript and protein following ischemia and reperfusion. Subsequent exposure of gene-targeted mice for each individual adenosine receptor to liver ischemia and reperfusion revealed a selective role for the Adora2b in liver protection. Moreover, treatment of wild-type mice with an Adora2b-selective antagonist resulted in enhanced liver injury, whereas Adora2b-agonist treatment was associated with attenuated hepatic injury in wild-type, but not in Adora2b(-/-) mice. Subsequent studies in mice with Adora2b deletion in different tissues--including vascular endothelia, myeloid cells, and hepatocytes--revealed a surprising role for hepatocellular-specific Adora2b signaling in attenuating nuclear factor NF-κB activation and thereby mediating liver protection from ischemia and reperfusion injury. These studies provide a unique role for hepatocellular-specific Adora2b signaling in liver protection during ischemia and reperfusion injury.

Author List

Zimmerman MA, Grenz A, Tak E, Kaplan M, Ridyard D, Brodsky KS, Mandell MS, Kam I, Eltzschig HK


Michael A. Zimmerman MD, FACS Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Gene Expression Profiling
Mice, Knockout
NF-kappa B
Receptor, Adenosine A2B
Reperfusion Injury
Signal Transduction
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0