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Protection from ischemic liver injury by activation of A_2A adenosine receptors during reperfusion: inhibition of chemokine induction

¹Cardiovascular Division, Department of Internal Medicine and Cardiovascular Research Center, ²Department of Molecular Physiology and Biological Physics, ³Nephrology Division, Department of Internal Medicine, and ⁴Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908

Submitted 11 August 2003 ; accepted in final form 9 September 2003

Ischemia-reperfusion (I/R) injury occurs as a result of restoring blood flow to previously hypoperfused vessels or after tissue transplantation and is characterized by inflammation and microvascular occlusion. We report here that 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e), a selective agonist of the A_2A adenosine receptor (A_2AAR), profoundly protects mouse liver from I/R injury when administered at the time of reperfusion, and protection is blocked by the antagonist ZM241385. ATL146e lowers liver damage by 90% as assessed by serum glutamyl pyruvic transaminase and reduces hepatic edema and MPO. Most protection remains if ATL146e treatment is delayed for 1 h but disappears when delayed for 4 h after the start of reperfusion. In mice lacking the A_2AAR gene, protection by ATL1465e is lost and ischemic injury of short duration is exacerbated compared with wild-type mice, suggesting a protective role for endogenous adenosine. I/R injury causes induction of hepatic transcripts for IL-1, IL-1, IL-1Ra, IL-6, IL-10, IL-18, INF-, INF-, regulated on activation, normal T cell expressed, and presumably secreted (RANTES), major intrinsic protein (MIP)-1, MIP-2, IFN--inducible protein (IP)-10, and monocyte chemotactic protein (MCP)-1 that are suppressed by administering ATL146e to wild-type but not to A_2AAR knockout mice. RANTES, MCP-1, and IP-10 are notable as induced chemokines that are chemotactic to T lymphocytes. The induction of cytokines may contribute to transient lymphopenia and neutrophilia that occur after liver I/R injury. We conclude that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A_2AAR activation. We speculate that inhibition of chemokine and cytokine production limits inflammation and contributes to tissue protection by the A_2AAR agonist ATL146e.

adenosine receptor; A_2A adenosine receptor knockout mice; P1 purinergic; receptors; regulated on activation, normal T cell expressed, and presumably excreted; monocyte chemotactic protein-1; interferon--inducible protein-10

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