Oxygen homeostasis, thiol equilibrium and redox regulation of signalling transcription factors in the alveolar epithelium

Abstract

There is growing evidence linking the pathophysiology of lung disease to an imbalance state of reduction–oxidation (redox) equilibrium. The therapeutic potential of glutathione, an ubiquitous sulfhydryl thiol, and its immunopharmacological properties in the airway epithelium bears clinical consequences for the paediatric treatment of respiratory distress (RD). Dynamic variation in alveolar pO 2 and its effect on redox state may impose a direct role in modulating the pattern of gene expression in lung tissues and, accordingly, could be pivotal in determining cellular fate under these conditions. Hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-κB (NF-κB) are redox-sensitive transcription factors of particular importance because their differential activation by reducing and oxidizing signals, respectively, regulate the expression/suppression of O 2-responsive genes. The regulation of these transcription factors, therefore, which is redox sensitive, is consistent with their roles in coordinating adaptive homeostatic responses to oxidative stress. Functionally, the relationship between O 2, glutathione biosynthesis and transcription factor activity bears typical implications for the pattern of cellular survivorship and alveolarization on exposure to O 2-linked stresses. In this review, I discuss (1) the HIF-1α/NF-κB responsiveness to dynamic changes in pO 2 characteristic of the transition period from placental to pulmonary-based respiration, (2) the capacity of the alveolar epithelium to engage in glutathione biosynthesis and redox shuttling, effectively forming a feedback mechanism governing gene expression, (3) the restitution of antioxidant/prooxidant equilibrium following oxidative challenge and its dependency on the adaptive coordination of responses between redox-associated signalling pathways controlling apoptosis and genetic regulatory factors and (4) a likely association between oxidative stress and the evolution of an inflammatory signal through the pleiotropic O 2-sensitive cytokines.