Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury

Abstract

The purine nucleoside adenosine is clinically employed in the treatment of supraventricular tachycardia. In addition, it has direct coronary vasodilatory effects, and may influence platelet aggregation. Experimental observations mechanistically link extracellular adenosine to cellular adaptation to hypoxia. Adenosine generation has been implicated in several pathophysiologic processes including angiogenesis, tumor defenses and neurodegeneration. In solid organ transplantation, prolonged tissue ischemia and subsequent reperfusion injury may lead to profound graft dysfunction. Importantly, conditions of limited oxygen availability are associated with increased production of extracellular adenosine and subsequent tissue protection. Within the rapidly expanding field of adenosine biology, several enzymatic steps in adenosine production have been characterized and multiple receptor subtypes have been identified. In this review, we briefly examine the biologic steps involved in adenosine generation and chronicle the current state of adenosine signaling in hepatic ischemia and reperfusion injury.

Keywords: Adenosine signaling; ischemia; liver; reperfusion.

Figure 1. Extracellular adenosine signaling

Extracellular adenosine is generated from enzymatic conversion of the precursor nucleotides ATP and ADP to AMP through the enzymatic activity of the ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and the subsequent conversion of AMP to adenosine through ecto-5′-nucleotidase (CD73). Extracellular adenosine can signal through four distinct adenosine receptors: ADORA1 (A₁), ADORA2A (A_2A), ADORA2B (A_2B), and ADORA3 (A₃). Adapted from the New England Journal of Medicine with permission.