Figure 9

[AQ27] Schematic diagram of NF-κB activation circuits and oxygen-signaling mechanisms in hyperoxia. Blocking reduction of oxidized glutathione (GSSG) to GSH, by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), leads to increasing intracellular stores of GSSG, a potent inhibitor of NF-κB transcription factor DNA binding. The pathway leading to the formation of GSH by the action of γ-glutamylcysteine synthetase (γ-GCS) is blocked by _L-buthionine-(S,R)-sulfoximine (BSO), inducing an irreversible inhibition of NF-κB activation. ROS are key components of the pathways leading to the activation of NF-κB, whose binding activity is obliterated by N-acetyl-_L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), potent scavengers of ROS. Although NAC elevates [GSH], it is unknown whether this mechanism induces NF-κB activation independently from the antioxidant effects of this inhibitor. PDTC elevates GSSG concentration by GSH oxidation, a pro-oxidant effect characteristic of dithiocarbamates, thereby mediating NF-κB inhibition. Upon NF-κB DNA binding, cascades of hyperoxia-responsive genes are activated, which have the potential to modulate cellular response to oxidative injury.