Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology

Respiratory Research

John J Haddad¹ 

[1] Severinghaus-Radiometer Research Laboratories, Molecular Neuroscience Research Division, Department of Anesthesia and Perioperative Care, University of California at San Francisco, School of Medicine, Medical Sciences Building S-261, 513 Parnassus Avenue, San Francisco, California 94143-0542, USA

关键词: redox equilibrium;    pathophysiology;    oxygen sensing;    NF-κB;    immunopharmacology;    HIF-1α;    glutathione;    development;    cytokine;    apoptosis;   

Others  :  1227393
DOI  :  10.1186/rr190

 received in 2002-02-25, accepted in 2002-07-15,  发布年份 2002

【 摘 要 】

How do organisms sense the amount of oxygen in the environment and respond appropriately when the level of oxygen decreases? Oxygen sensing and the molecular stratagems underlying the process have been the focus of an endless number of investigations trying to find an answer to the question: "What is the identity of the oxygen sensor?" Dynamic changes in pO₂ constitute a potential signaling mechanism for the regulation of the expression and activation of reduction-oxidation (redox)-sensitive and oxygen-responsive transcription factors, apoptosis-signaling molecules and inflammatory cytokines. The transition from placental to lung-based respiration causes a relatively hyperoxic shift or oxidative stress, which the perinatal, developing lung experiences during birth. This variation in ΔpO₂, in particular, differentially regulates the compartmentalization and functioning of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-κB (NF-κB). In addition, oxygen-evoked regulation of HIF-1α and NF-κB is closely coupled with the intracellular redox state, such that modulating redox equilibrium affects their responsiveness at the molecular level (expression/transactivation). The differential regulation of HIF-1α and NF-κB in vitro is paralleled by oxygen-sensitive and redox-dependent pathways governing the regulation of these factors during the transition from placental to lung-based respiration ex utero. The birth transition period in vivo and ex utero also regulates apoptosis signaling pathways in a redox-dependent manner, consistent with NF-κB being transcriptionally regulated in order to play an anti-apoptotic function. An association is established between oxidative stress conditions and the augmentation of an inflammatory state in pathophysiology, regulated by the oxygen- and redox-sensitive pleiotropic cytokines.

【 授权许可】

   
2003 Haddad, licensee BioMed Central Ltd

【 图 表 】

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