Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases

HK Eltzschig, DL Bratton, SP Colgan - Nature Reviews Drug Discovery, 2014 - nature.com
HK Eltzschig, DL Bratton, SP Colgan
Nature Reviews Drug Discovery, 2014nature.com
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 …
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.
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