Hypoxia and inflammation often occur concomitantly, and together, result in profound changes in tissue metabolism. Such "inflammatory hypoxia" results, at least in part, from active recruitment of energy and oxygen demanding inflammatory cell types. In the past several years, we have focused on defining molecular pathways and functional targets for endothelial hypoxia. Results from these studies have identified a novel series of pathways in which hypoxia (both in vitro and in vivo) drives the coordinated metabolism of extracellular nucleotides. These studies have identified endogenous anti-inflammatory properties of hypoxia-induced adenosine (Ado) signaling. Initial insight gained from global transcriptional arrays identified the prominent regulation of surface enzymes (CD39, CD73, adenosine deaminase), nucleotide transporters (ENT1 and ENT2) and Ado receptors (esp. A2B subtype) critical for the regulated metabolism and signaling of Ado. Central to this pathway was the identification of hypoxia-inducible factor (HIF) binding and regulation of each of these gene promoters, thus identifying HIF as an endogenous anti-inflammatory molecule. Ongoing studies have revealed that Ado functions as an endogenous protective agent mediating multiple anti-inflammatory endpoints. Ongoing studies have identified the basis of Ado-mediated anti-inflammation. Studies addressing regulation of HIF-11 and NF-:B revealed that Ado activates HIF-11 and inhibits NF-:B through the active deneddylation of Cullins, a family of proteins critical for the recruitment ubiquitin ligases. Based on these preliminary studies, we hypothesize that Ado functions as an endogenous anti-inflammatory through direct actions on vascular HIF and NF-:B.
Three specific aims are directed at testing this hypothesis:
In Specific Aim 1, we will probe the contribution of individual Ado receptor subtypes to Ado actions on HIF and NF-:B via Cullin deneddylation.
Specific Aim 2 will extend extensive preliminary data to elucidate mechanisms of Ado-mediated Cullin deneddylation.
Specific Aim 3 will build on preliminary studies to define endpoints of Ado-mediated Cullin deneddylation via PHD inhibition. The overall aim of this proposal is to elucidate the metabolic signaling events mediating Ado vascular responses during inflammatory hypoxia. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

Public Health Relevance

Studies outlined here build on existing work related to acute and chronic inflammatory disease. In particular, these studies are designed to identify, test and unify hypotheses that adenosine functions as an endogenous anti-inflammatory through distinct mechanisms.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Charette, Marc F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Campbell, Eric L; Bruyninckx, Walter J; Kelly, Caleb J et al. (2014) Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40:66-77
Weissmuller, Thomas; Glover, Louise E; Fennimore, Blair et al. (2014) HIF-dependent regulation of AKAP12 (gravin) in the control of human vascular endothelial function. FASEB J 28:256-64
Keely, S; Campbell, E L; Baird, A W et al. (2014) Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol 7:114-23
Kominsky, Douglas J; Campbell, Eric L; Ehrentraut, Stefan F et al. (2014) IFN-?-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia. J Immunol 192:1267-76
Eckle, Tobias; Kewley, Emily M; Brodsky, Kelley S et al. (2014) Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol 192:1249-56
Eltzschig, Holger K; Bratton, Donna L; Colgan, Sean P (2014) Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13:852-69
Colgan, Sean P; Fennimore, Blair; Ehrentraut, Stefan F (2013) Adenosine and gastrointestinal inflammation. J Mol Med (Berl) 91:157-64
Kelly, C J; Glover, L E; Campbell, E L et al. (2013) Fundamental role for HIF-1* in constitutive expression of human * defensin-1. Mucosal Immunol 6:1110-8
Colgan, Sean P; Ehrentraut, Stefan F; Glover, Louise E et al. (2013) Contributions of neutrophils to resolution of mucosal inflammation. Immunol Res 55:75-82
Colgan, Sean P; Curtis, Valerie F; Campbell, Eric L (2013) The inflammatory tissue microenvironment in IBD. Inflamm Bowel Dis 19:2238-44

Showing the most recent 10 out of 63 publications