Environmental toxicity, redox signaling and lung inflammation: The role of glutathione

Abstract

Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H2O2 as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox sensitive transcription factors such as Nrf2, NF-κB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-L-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease.

Endogeous sulfur dioxide protects against oleic acid-induced acute lung injury in association with inhibition of oxidative stress in rats

“…30 ROS and RNS play important roles in regulating cell survival, and a sudden excessive and prolonged surge of ROS/RNS could induce cell death. 31 In most tissues, the first line of defense against oxidative stress is the endogenous antioxidant defense system such as SODs: SOD1 in the cytoplasm, SOD2 in mitochondria, and SOD3 in the extracellular space. 32 Furthermore, free radical insult might activate PARP and culminate in an apoptotic cascade.…”

Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells

“…Effects of FP and CARB on GSH expression in bronchial epithelial cells GSH is one of the most important defensive mechanisms against oxidative stress (Biswas and Rahman 2009;Ghezzi 2011). The effect of CARB and FP on GSH expression in CSE-stimulated bronchial epithelial cells was explored.…”

S-Carboxymethylcysteine inhibits adherence of Streptococcus pneumoniae to human alveolar epithelial cells

“…S-CMC-Lys has an antioxidant action that leads to a significant increase of glutathione (GSH) flux through the cell membrane (Guizzardi et al, 2006;Garavaglia et al, 2008). Such an increase in intracellular GSH induces a reduction in inflammatory cytokine release through inhibition of NFkB activation (Aoki et al, 1996;Antonicelli et al, 2002;Biswas & Rahman, 2009). A previous study reported that the pyrrolidine derivative pyrrolidine dithiocarbamate, an NFkB inhibitor, reduces acid-induced S. pneumoniae adherence to A549 cells via inhibition of PAFR induction (Ishizuka et al, 2001).…”