Hypoxic tissue conditions occur during a number of inflammatory diseases and are associated with the breakdown of barriers and induction of proinflammatory responses. At the same time, hypoxia is also known to induce several adaptive and tissue-protective pathways that dampen inflammation and protect tissue integrity. Hypoxia-inducible factors (HIFs) that are stabilized during inflammatory or hypoxic conditions are at the center of mediating these responses. In the past decade, several genes regulating extracellular adenosine metabolism and signaling have been identified as being direct targets of HIFs. Here, we discuss the relationship between inflammation, hypoxia, and adenosine and that HIF-driven adenosine metabolism and signaling is essential in providing tissue protection during inflammatory conditions, including myocardial injury, inflammatory bowel disease, and acute lung injury. We also discuss how the hypoxia-adenosine link can be targeted therapeutically in patients as a future treatment approach for inflammatory diseases.

Ecto-5'-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell-mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization-dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42-dependent conformational change of the actin-related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, β-catenin, and Na(+)K(+) ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described.

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Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients.