Hypoxia signaling during intestinal ischemia and inflammation

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.

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.

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.