Oxygen-sensitive pro-inflammatory cytokines, apoptosis signaling and redox-responsive transcription factors in development and pathophysiology.
The transition from placental to pulmonary-based respiration causes a relative hyperoxic shift, or oxidative stress, which the perinatal developing-lung experiences during birth. Dynamic changes in pO2, therefore, constitute a potential signaling mechanism for the regulation of the expression/activation of reduction-oxidation (redox)-sensitive and O2-responsive transcription factors, apoptosis signaling and pro-inflammatory cytokines. The variation in deltaPO2, in particular, differentially regulates the compartmentalization and function of the transcription factors hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear factor-kappaB (NF-kappaB). In addition, O2-evoked regulation of HIF-1alpha and NF-kappaB is closely coupled with the intracellular redox state, such that modulating redox equilibrium affects their expression/activation. The differential regulation of HIF-1alpha and NF-kappaB in vitro is paralleled by O2- and redox-dependent pathways governing the regulation of these factors during the transition from placental to pulmonary-based respiration ex vivo. Furthermore, the birth transition period in vitro and ex vivo regulates apoptosis signaling pathways in a redox-dependent manner, consistent with NF-kappaB playing an anti-apoptotic function. An association is established between an oxidative stress condition and the augmentation of a pro-inflammatory state in pathophysiology, regulated by the O2- and redox-sensitive pleiotropic cytokines.
Haddad
J J
JJ
Department of Anesthesia and Perioperative Care, University of California at San Francisco, School of Medicine, 94143-0542, USA. haddadj@anesthesia.ucsf.edu
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008168:Lung / Q000473:pathology; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D005979:Glutathione Peroxidase; D005978:Glutathione; D010100:Oxygen