Glutathione Redox Control of Asthma: From Molecular Mechanisms to Therapeutic Opportunities

Abstract

Asthma is a chronic inflammatory disorder of the airways associated with airway hyper-responsiveness and airflow limitation in response to specific triggers. Whereas inflammation is important for tissue regeneration and wound healing, the profound and sustained inflammatory response associated with asthma may result in airway remodeling that involves smooth muscle hypertrophy, epithelial goblet-cell hyperplasia, and permanent deposition of airway extracellular matrix proteins. Although the specific mechanisms responsible for asthma are still being unraveled, free radicals such as reactive oxygen species and reactive nitrogen species are important mediators of airway tissue damage that are increased in subjects with asthma. There is also a growing body of literature implicating disturbances in oxidation/reduction (redox) reactions and impaired antioxidant defenses as a risk factor for asthma development and asthma severity. Ultimately, these redox-related perturbations result in a vicious cycle of airway inflammation and injury that is not always amenable to current asthma therapy, particularly in cases of severe asthma. This review will discuss disruptions of redox signaling and control in asthma with a focus on the thiol, glutathione, and reduced (thiol) form (GSH). First, GSH synthesis, GSH distribution, and GSH function and homeostasis are discussed. We then review the literature related to GSH redox balance in health and asthma, with an emphasis on human studies. Finally, therapeutic opportunities to restore the GSH redox balance in subjects with asthma are discussed.

Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases

“…Therefore, oxidation of critical proteins located in the AM plasma membrane may render them inactive. By restoring the extracellular GSH pool, these critical cysteines facing the lining fluid may then be reduced and restored to their active state for catalytic activity or signaling related to AM phagocytosis (25,61). Likewise, intracellular proteins also contain redox-sensitive sites.…”

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

“…GSH is the predominant antioxidant in airway cells, ranging from 1 to 11 mM depending on the subcellular compartment, and its concentration in the epithelial lining fluid (ELF) that bathes the entire surface of the lung, is over 100-fold higher than in plasma [91][92][93]. GSH is a key player in the maintenance of redox homeostasis in the lung, which is mainly defined by the ratio of the concentration of its reduced form to its disulphide form, GSH/GSSG [94]. Under normal conditions, the oxidized form represents less than 1% of the total GSH pool; however, alterations of the GSH/GSSG ratio in ELF have been described in patients with asthma and other inflammatory disorders such as cystic fibrosis.…”

Plasma total thiol pool in children with asthma: Modulation during montelukast monotherapy

“…Disturbances in oxidation/reduction reactions and impaired antioxidant defences are considered risk factors for asthma development and asthma severity. 3 Thiol compounds are powerful antioxidants that are present in high concentrations in intracellular and extracellular fluids and they react with almost all physiological oxidants. 4,5 They can also function as electron or hydrogen donors to scavenge free radicals and repair damaged molecules.…”