The hypoxia-inflammation link and potential drug targets

Abstract

Purpose of review: Hypoxia represents one of the strongest transcriptional stimuli known to us. In most cases, hypoxia-induced changes in gene expression are directed towards adapting tissues to conditions of limited oxygen availability.

Recent findings: As a well known example, physical exercise at high altitude results in the transcriptional induction of erythropoietin that functions to increase oxygen carrying capacity and red cell volume. Studies of the transcriptional pathway responsible for the induction of erythropoietin during conditions of hypoxia led to the discovery of the transcription factor hypoxia-inducible factor (HIF) that is known today as the key transcription factor for hypoxia adaptation. Surgical patients are frequently at risk for experiencing detrimental effects of hypoxia or ischemia, for example, in the context of acute kidney injury, myocardial, intestinal or hepatic ischemia, acute lung injury, or during organ transplantation.

Summary: In the present review, we discuss the mechanisms of transcriptional adaptation to hypoxia and provide evidence supporting the hypothesis that targeting hypoxia-induced inflammation can represent novel pharmacologic strategies to improve perioperative outcomes. Currently, such strategies are being explored at an experimental level, but we hope that some of these targets can be translated into perioperative patient care within the next decade.

Figure 1

Overview of clinical conditions characterized primarily by tissue hypoxia resulting in inflammatory changes (left), or inflammatory diseases that lead to tissue hypoxia (right; from the New England Journal of Medicine with permission).

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

In normoxia, hydroxylation at 2 proline residues promotes HIF-α association with pVHL and HIF-α destruction via the ubiquitin/proteasome pathway, while hydroxylation of an asparagine residue blocks association with coactivators. In hypoxia, these processes are suppressed, allowing HIF-α subunits (both HIF-1α and HIF-2α) to escape proteolysis, dimerize with HIF-1β, recruit coactivators, and activate transcription via HREs. N, asparagine; P, proline; OH, hydroxyl group; Ub, ubiquitin [modified, from the Journal of Clinical Investigation with permission ].