针对缺氧信号通路治疗缺血性和炎症性疾病。
Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.
机构信息
Organ Protection Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
出版信息
Nat Rev Drug Discov. 2014 Nov;13(11):852-69. doi: 10.1038/nrd4422.
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.
摘要
缺氧诱导因子 (HIFs) 在与疾病相关的不利炎症过程中稳定下来，例如炎症性肠病、病原体感染和急性肺损伤，以及在缺血再灌注损伤期间。HIF 的稳定和缺氧诱导的基因表达变化对炎症组织微环境和疾病结果有深远的影响。尽管启动 HIF 稳定的机制可能有所不同，但控制 HIF 稳定的最终分子步骤都集中在一组氧感应脯氨酰羟化酶 (PHD) 上，这些酶将 HIF 标记为蛋白酶体降解。因此，PHD 是很有前途的治疗靶点。在这篇综述中，我们讨论了靶向 PHD-HIF 通路治疗炎症性和缺血性疾病的新出现的潜力和相关挑战。
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