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Nat Rev Drug Discov. 2014 Nov;13(11):852-69. doi: 10.1038/nrd4422.

Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.

Author information

1
Organ Protection Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
2
Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
3
Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.

Abstract

Hypoxia-inducible factors (HIFs) are stabilized during adverse inflammatory processes associated with disorders such as inflammatory bowel disease, pathogen infection and acute lung injury, as well as during ischaemia-reperfusion injury. HIF stabilization and hypoxia-induced changes in gene expression have a profound impact on the inflamed tissue microenvironment and on disease outcomes. Although the mechanism that initiates HIF stabilization may vary, the final molecular steps that control HIF stabilization converge on a set of oxygen-sensing prolyl hydroxylases (PHDs) that mark HIFs for proteasomal degradation. PHDs are therefore promising therapeutic targets. In this Review, we discuss the emerging potential and associated challenges of targeting the PHD-HIF pathway for the treatment of inflammatory and ischaemic diseases.

PMID:
25359381
PMCID:
PMC4259899
DOI:
10.1038/nrd4422
[Indexed for MEDLINE]
Free PMC Article

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