Interplay of hypoxia and A2B adenosine receptors in tissue protection

That adenosine signaling can elicit adaptive tissue responses during conditions of limited oxygen availability (hypoxia) is a long-suspected notion that recently gained general acceptance from genetic and pharmacologic studies of the adenosine signaling pathway. As hypoxia and inflammation share an interdependent relationship, these studies have demonstrated that adenosine signaling events can be targeted to dampen hypoxia-induced inflammation. Here, we build on the hypothesis that particularly the A(2B) adenosine receptor (ADORA(2B)) plays a central role in tissue adaptation to hypoxia. In fact, the ADORA(2B) requires higher adenosine concentrations than any of the other adenosine receptors. However, during conditions of hypoxia or ischemia, the hypoxia-elicited rise in extracellular adenosine is sufficient to activate the ADORA(2B). Moreover, several studies have demonstrated very robust induction of the ADORA(2B) elicited by transcriptional mechanisms involving hypoxia-dependent signaling pathways and the transcription factor "hypoxia-induced factor" 1. In the present chapter, genetic and pharmacologic evidence is presented to support our hypothesis of a tissue protective role of ADORA(2B) signaling during hypoxic conditions, including hypoxia-elicited vascular leakage, organ ischemia, or acute lung injury. All these disease models are characterized by hypoxia-elicited tissue inflammation. As such, the ADORA(2B) has emerged as a therapeutic target for dampening hypoxia-induced inflammation and tissue adaptation to limited oxygen availability.