Hypoxia signaling during intestinal ischemia and inflammation

Abstract

Purpose of review: During critical illness, alterations of intestinal blood supply and inflammatory activation can result in severe intestinal hypoxia (limited oxygen availability). Conditions of hypoxia lead to the activation of a transcriptional program that is under the control of the transcription factor hypoxia-inducible factor (HIF). In many instances, HIF-dependent alterations of gene expression represent endogenous adaptive responses that dampen pathologic inflammation and could be targeted to treat intestinal injury.

Recent findings: Post-translational stabilization of the HIF transcription factor and corresponding changes in gene expression are central to the resolution of intestinal injury. Examples for such responses that we discuss in this review include hypoxia-elicited increases in extracellular adenosine production and signaling, particularly through the A2B adenosine receptor, and intestinal protection provided by hypoxia-inducible netrin-1.

Summary: The present review focuses on HIF-elicited anti-inflammatory pathways that result in intestinal protection during critical illness. Many of these pathways represent novel therapeutic targets for attenuating multiorgan failure and critical illness. Whereas these therapeutic approaches are currently being investigated in cell culture models or in genetic mouse models, we are optimistic that at least some of these novel targets can be translated from bench to bedside in the near future.

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 [19▪]).

FIGURE 2

Extracellular signaling of ATP and adenosine during ischemia or inflammation. Multiple cell types release ATP during ischemia and reperfusion (e.g. spillover from necrotic cells or controlled release through pannexin hemichannels from apoptotic cells or connexin hemichannels from activated inflammatory cells). Subsequent binding of ATP to P2 receptors enhances pathological inflammation and tissue injury, for example, through P2X7-dependent Nlrp3 inflammasome activation and P2Y6-dependent enhancement of vascular inflammation. ATP can be rapidly converted to adenosine through the ecto-apyrase CD39 (conversion of ATP to AMP) and subsequently by the ecto-5′ nucleotidase CD73 (conversion of AMP to adenosine). Adenosine signaling dampens sterile inflammation, enhances metabolic adaptation to limited oxygen availability and promotes the resolution of injury through activation of A2A adenosine receptors expressed on inflammatory cells and activation of A2B adenosine receptors expressed on tissue-resident cells (e.g. cardiac myocytes, vascular endothelia or intestinal epithelia). EC, endothelial cell; VSMC, vascular smooth muscle cell. (from Nature Medicine with permission [18▪]).