Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology.
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 DeltapO2, in particular, differentially regulates the compartmentalization and functioning of the transcription factors hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear factor-kappaB (NF-kappaB). In addition, oxygen-evoked regulation of HIF-1alpha and NF-kappaB 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-1alpha and NF-kappaB 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-kappaB 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.
Haddad
John J
JJ
Severinghaus-Radiometer Research Laboratories, Molecular Neuroscience Research Division, Department of Anesthesia and Perioperative Care, University of California at San Francisco, School of Medicine, 94143-0542, USA. johnjhaddad@yahoo.co.uk
D000818:Animals; D047109:Fetal Development / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism* / Q000503:physiopathology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D014157:Transcription Factors; D010100:Oxygen