Oxygen-sensitive pro-inflammatory cytokines, apoptosis signaling and redox-responsive transcription factors in development and pathophysiology.

Abstract

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.