Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation.

Kiers, Dorien; Wielockx, Ben; Peters, Esther; van Eijk, Lucas T; Gerretsen, Jelle; John, Aaron; Janssen, Emmy; Groeneveld, Rianne; Peters, Mara; Damen, Lars; Meneses, Ana M; Krüger, Anja; Langereis, Jeroen D; Zomer, Aldert L; Blackburn, Michael R; Joosten, Leo A; Netea, Mihai G; Riksen, Niels P; van der Hoeven, Johannes G; Scheffer, Gert-Jan; Eltzschig, Holger K; Pickkers, Peter; Kox, Matthijs

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients.