Targeting Hypoxia Signaling for Perioperative Organ Injury

Abstract

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.

Figure 1. Links between hypoxia and inflammation in perioperative organ injury

Left side of this figure shows examples of clinical conditions characterized by tissue hypoxia, which causes inflammation, including pulmonary edema, acute kidney injury, and ischemia/reperfusion injury. Inflammatory diseases that lead to tissue hypoxia are demonstrated in the right side of the figure, including acute lung injury, acute gut injury, and infection with pathogens. The interdependent relationship between inflammation and hypoxia renders HIF activation a desirable therapeutic intervention for perioperative organ injury. Figure is adapted from Hypoxia and Inflammation; Eltzschig H.K., and Carmeliet, P., N Engl J Med 2011, 364(7): 656–665. Copyright © (2011) Massachusetts Medical Society (6).

Figure 2. Regulation of hypoxia-inducible factor (HIF) protein levels under normoxic or hypoxic conditions

Under normoxic conditions, hydroxylation at 2 proline residues by prolyl hydroxylases (PHDs) promotes HIF-α association with VHL and leads to HIF-α destruction via the ubiquitin/proteasome pathway. In hypoxia, these processes are suppressed, allowing HIF-α subunits (both HIF-1α and HIF-2α) to escape proteolysis, dimerize with HIF-1β, translocate to the nucleus, and activate transcription via hypoxia-response element (HREs). HIF activation by PHD inhibitors, conservative oxygenation, ischemic preconditioning (IPC), and remote ischemic preconditioning (RIPC) can be potential therapeutic approaches for perioperative organ injury.

Figure 3. Control of extracellular adenosine generation and signaling during inflammation by hypoxia

During inflammatory conditions, multiple cell types release nucleotides, including activated inflammatory cells, apoptotic cells and necrotic cells, typically in the form of adenosine triphosphate (ATP) or adenosine diphosphate (ADP) from the intracellular compartment into the extracellular space. In acute organ injury, a decrease in oxygen supply (e.g., due to vessel thrombosis) and significant increases in oxygen demand result in an imbalance in oxygen availability. Hypoxia causes Sp1-dependent induction of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) (23), and a hypoxia-inducible factor (HIF)–dependent induction of ecto-5’nucleotidase (CD73) (24). Extracellular adenosine is generated primarily from the enzymatic conversion of ATP and ADP by CD39 and CD73. Extracellular adenosine can signal through four distinct adenosine receptors: adenosine A₁ receptor (A1R), adenosine A_2A receptor (A2AR), adenosine A_2B receptor (A2BR), and adenosine A₃ receptor (A3R). For example, activation of A2AR on inflammatory cells such as neutrophils (147) or lymphocytes attenuates inflammation (–150). As shown in other experimental studies, signaling events through A2BR facilitates tissue adaptation to hypoxia and attenuation of acute lung injury and ischemia/ reperfusion injury (41,57). Activation of adenosine A2AR (136) and A2BR (151) dampen intestinal inflammation and promote epithelial integrity during intestinal inflammation. Current study suggested that adenosine receptor agonist has therapeutic potential to prevent and treat perioperative organ injury. Figure is adapted from Purinergic Signaling during Inflammation; Holger K. Eltzschig, Michail V. Sitkovsky, and Simon C. Robson, N Engl J Med 2012; 367:2322–2333 © (2012) Massachusetts Medical Society (27).

Figure 4. The “Yin and Yang” of oxygenation in the perioperative setting

In the clinical setting, utilizing high oxygen concentrations ("Hyperoxia") during the perioperative period or in critical care patients may be associated with an increased "safety margin" to avoid perioperative hypoxia and hypoxia-driven organ injury. On the other hand, hyperoxia has been implicated in promoting tissue injury by elevating levels of reactive oxygen species, and some clinical studies suggest worse outcomes associated with such approaches. At the same time, utilizing high inspired oxygen concentrations, has the potential to dampen tissue-protective and anti-inflammatory pathways under the control of hypoxia-inducible transcription factors (HIFs), such as extracellular adenosine signaling. There appears to be a "Yin and Yang" with a U-shaped relationship between hyperoxia and conservative oxygen therapy. It will be critical for the perioperative field to find the "optimal oxygen concentration" for individual clinical scenarios. Different clinical studies have indicated that conservative oxygen therapy can be utilized safely in surgical or critical care patients, without increasing the risk of organ injury or wound infections. While we are awaiting the results of larger scale trials, the current evidence indicates oxygen conservative therapy as safe and associated with better outcomes - at least in some of the measurements. In the context of the current review, some of the improved outcomes with conservative oxygen therapy could potentially be mediated by a more robust activation of the "HIF" pathway and concomitant organ protection.