Targeting purinergic signaling for perioperative organ protection.

1001 May 2013 A D VA N C E M E N T S in the field of anesthesia have led to significant improvements in our monitoring capabilities, safer anesthetic drugs, and improved pain control. Despite this remarkable progress, acute organ injury remains one of the leading causes for morbidity and mortality in surgical patients. Patients who require a major surgical intervention—such as cardiothoracic, vascular, general surgery, or solid organ transplantation—may have had a “perfect” operation but are threatened during their perioperative course by the development of acute organ injury. For example, acute kidney injury, myocardial infarction, intestinal ischemia, and reperfusion injury or stroke are some of the threats that are among the leading causes of perioperative morbidity and mortality.1 A recent review article published in the New England Journal of Medicine discussed “Purinergic Signaling during Inflammation,”2 provides an update on how signaling events through extracellular receptors for the purines adenosine triphosphate (ATP) and adenosine can be targeted to alter inflammatory endpoints. As discussed in this review article, recent studies implicate purinergic signaling via ATP or adenosine receptors as important therapeutic targets to prevent or treat acute organ injury in perioperative patients. In many instances, perioperative organ injury is caused by ischemia and concomitant hypoxia-induced inflammation.3 Hypoxia and inflammation share an interdependent relationship, where inflammatory diseases such as intestinal inflammation or acute lung injury can cause inflamed areas to become severely hypoxic. This typically occurs because of increased metabolic demand of resident and inflammatory cells while metabolic supply is simultaneously decreased. However, diseases that are attributed primarily to hypoxia and ischemia will undergo secondary inflammatory changes that—in the context of ischemia and reperfusion injury— contribute significantly to organ injury (fig. 1).1 During hypoxic or inflammatory disease states, many cells release ATP from their intracellular toward the extracellular compartment. In the extracellular space, ATP can activate extracellular ATP receptors, which are classified as P2 receptors. They function as G-protein coupled receptors (P2Y receptors) or as ligand-gated ion channels (P2X receptors). Activation of P2 receptors has been shown to cause inflammatory activation and organ injury during ischemia or inflammation, and therapeutic strategies to dampen ATP receptor activation have been implicated in the treatment of inflammatory diseases.4–6 In the extracellular compartment, ATP is rapidly converted to adenosine. In contrast to the proinflammatory functions of ATP receptors, adenosine receptors have been shown to attenuate hypoxic inflammation,7 provide metabolic tissue adaptation to increase ischemia tolerance,8 and to promote injury resolution.9–11 Therefore, treatment approaches to enhance ATP conversion to adenosine represents an experimental therapeutic strategy to dampen acute organ injury. Conversion of ATP to adenosine is controlled by a two-step enzymatic system. The first step is the conversion of ATP to adenosine monophosphate by the ectonucleoside triphosphate diphosphohydrolase 1 (CD39). The subsequent second step in the extracellular generation of adenosine is catalyzed by the ecto-5′-nucleotidase CD73. Conditions of inflammatory hypoxia result in the induction of both enzymes (fig. 2). CD39 is transcriptionally induced by the Sp1 transcription factor,12 whereas CD73 is induced by hypoxia-inducible factor (HIF)—the key transcription factor for hypoxia adaptation.13,14 For example, HIF is known to regulate the transcriptional activity of the erythropoietin promoter. Conditions of hypoxia, ischemia, or anemia will lead to tissue hypoxia and subsequent stabilization of HIF. Binding of HIF to the erythropoietin promoter results in transcriptional induction of erythropoietin, leading to increases in erythropoiesis. Indeed, HIF activators have been implicated in treating inflammatory hypoxia via increasing tissue expression of CD73, thereby promoting the extracellular generation of adenosine.5 Once generated in the extracellular compartment, adenosine can activate four distinct adenosine receptors. These Targeting Purinergic Signaling for Perioperative Organ Protection