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Figure 12 | Respiratory Research

Figure 12

From: Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology

Figure 12

Oxygen- and redox-mediated pathways regulating cytokines. (A) Schematic representation of the pathways leading to the generation of reactive oxygen species (ROS) and their selective dismutation. A number of major cellular enzymes that defend against oxidative stress have been conserved through evolution. Superoxide (O2 -•) anion is metabolized via the dismutation reaction 2O2 -• + 2H+ → O2 + H2O2. The reaction is catalyzed by superoxide oxidoreductase dismutase (SOD), which is both a cytoplasmic enzyme that is constitutively expressed and a mitochondrial enzyme that is induced in response to oxidant stress. The H2O2 produced by the dismutation of O2 -• is converted by catalase (CAT) in peroxisomes to H2O and O2 and by glutathione peroxidase (GSH-PX) in the cytoplasm, at the expense of reduced glutathione (GSH). This leads to the formation of oxidized glutathione disulphide (GSSG) that is recycled back to GSH by glutathione reductase (GSSG-RD). H2O2 could be further converted by another pathway involving iron (Fe2+) into hydroxyl radical (•OH), an injurious ROS causing cellular damage. This iron-catalyzed reaction, known as the Fenton-like reaction, is impeded by the iron chelator desferrioxamine (DSF), which is also capable of neutralizing the toxicity of •OH. (B) Schematic model of thiol regulation of chemioxyexcitation-induced cytokine secretion in the alveolar epithelium. The predominant form of intracellular glutathione is GSH, which is synthesized by γ-glutamylcysteine synthetase (γ-GCS). The molecules 2-oxothiazolidine-4-carboxylate (OTC), S-adenosyl-L-methionine (SAM) and N-acetyl-L-cysteine are major precursors of cysteine, the rate-limiting substrate in the biosynthesis of GSH, a pathway which is selectively blocked by L-buthionine-(S,R)-sulfoximine (BSO). BSO upregulates the formation of intracellular ROS, which are major inducers of cytokine secretion. GSH is either rapidly exported, where the membrane-bound γ-glutamyl transpeptidase (γ-GT) degrades it into its subcellular components to be used for resynthesis, or is converted by oxidation to glutathione disulphide (GSSG) by glutathione peroxidase (GSH-PX) and its mimetic ebselen, at the expense of ROS (which are promptly detoxified to form peroxides, ROOH). The formation of GSSG and/or reduction of ROS downregulate the chemioxyexcitation-dependent cytokine release. GSSG is rapidly recycled back into GSH by glutathione reductase (GSSG-RD), a pathway which is selectively blocked by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU). The block leads to accumulation of GSSG, which, along with pyrrolidine dithiocarbamate, a precursor of GSSG, downregulates the formation of ROS and abrogates the cytokine-dependent sequelae. Cytokines act as major participants in the pathophysiology and aggravation of the clinical symptoms of respiratory distresses (RD).

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