Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

Abstract

Background Glutathione S-transferase Pi (GSTPi) is the predominant redox regulator in the lung. While evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive. Objectives To determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis. Methods We elucidated the regulation of GSTPi in children with asthma and utilized murine models of asthma to determine the role of GSTPi in redox homeostasis. Measurements and Main Results Our findings demonstrate that GSTPi transcript levels are markedly down-regulated in allergen and IL-13 treated mouse models of asthma via STAT6 dependent and independent pathways. Nuclear factor-erythroid 2 related factor 2 (Nrf2) was also down-regulated in these models. The decrease in GSTPi expression was associated with decreased total GST activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating Cys oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in % cystine) compared with wild-type mice following allergen challenge. GSTPi expression was similarly down-regulated in children with asthma. Conclusions These data collectively suggest that down-regulation of GSTPi following allergen challenge may contribute to the asthma phenotype due to disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi may be an important therapeutic target for asthma, and evaluation of GSTPi expression may prove beneficial in identifying individuals who would benefit from therapy targeting this pathway.

Oxidative Processing of Latent Fas in the Endoplasmic Reticulum Controls the Strength of Apoptosis

“…These results suggest that excess H 2 O 2 produced by rapid oxidative processing of Fas is the cause of this oxidation, instead of Prx4 being an electron acceptor in FasL-induced oxidative processing. A recent body of work has clearly demonstrated the role of GSTs as regulators of molecular pathways that control cell division and apoptosis (1,38,51). Interestingly, GSTP1 has been shown to glutathionylate a 1-Cys peroxiredoxin, Prx6, during its regeneration cycle via an SOH intermediate (32).…”

Airway Epithelium Plays a Leading Role in the Complex Framework Underlying Respiratory Allergy

“…On the other hand, nuclear factor (erythroid-derived 2)-like 2 is a transcription factor that regulates the expression of phase II and antioxidant enzyme genes, for example, catalase, SOD, glutathione-S-transferase (GST), glutathione peroxidase (GPx), and glutathione synthetase, and is considered a feedback loop that is originally affected by dramatic changes in the GSH/GSSG ratio [1,97]. In this sense, GSTP1-and SOD-specific loci have been strongly associated with asthma and deficiencies in oxidant defenses, although their role remains unclear [98]. As for the protective role of GSH, it is noteworthy that GSH can also be reversibly incorporated into cysteine residues of proteins, through an enzymatic process called S-glutathionylation [99].…”

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

“…In mice and humans, it is clear that a number of intracellular signaling pathways are affected in the development of APAPinduced hepatotoxicity, such as oxidative stress (McGill et al, 2012), mitogen-activated protein (MAP) kinase phosphorylation (Gunawan et al, 2006), mitochondrial injury (Kon et al, 2004), and glutathione depletion (Henderson et al, 2000). Importantly, GSTP has been found to play a significant role in the regulation of a number of these signaling events (Henderson et al, 2000;Schroer et al, 2011;Castro-Caldas et al, 2012), and therefore it remains unclear why GSTP deletion confers resistance to APAP injury.…”