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.

FIG. 1.

The traditional concept of oxidative stress in health and disease. Originally, oxidative stress was thought to result from a global disruption in the pro-oxidant and antioxidant balance. In this view, disease was attributed to an increased burden of free radicals (thiyl radical [S^•], nitric oxide radical [NO^•], superoxide [O₂^•-], peroxynitrite [OONO–], and hydrogen peroxide) and a deficiency of endogenous antioxidants (glutathione, reduced [thiol] form [GSH], catalase, glutathione-S-transferase [GST], glutathione reductase [GR], superoxide dismutase [SOD], and glutathione peroxidase [GPX]).

FIG. 2.

A modified concept of oxidative stress. As opposed to a simple disruption in the pro-oxidant and antioxidant balance, oxidative stress is better conceptualized as a disruption of redox signaling and control. In this view, oxidative stress is a dynamic process in constant flux, similar to a pendulum. These oxidative shifts are highly compartmentalized and are not necessarily in equilibrium between the extracellular space, the cytoplasm, and the organelles.

FIG. 3.

Methionine metabolism. Methionine is metabolized to homocysteine, which is either (i) methylated back to methionine through the remethylation pathway or (ii) converted to cysteine through the trans-sulfuration pathway. The cysteine that is formed may be used for protein synthesis or formation of glutathione.

FIG. 4.

Chemical structures of cysteine (Cys) and cystine (CySS).

FIG. 5.

Chemical structures of GSH and glutathione disulfide (GSSG).

FIG. 6.

The γ-glutamyl transferase cycle. The γ-glutamyl cycle allows glutathione to serve as a continuous source of cysteine. The γ-glutamyl-cysteine and cysteinyl-glycine are broken down to form cysteine, which can be used for glutathione synthesis or protein incorporation.

FIG. 7.

The role of glutathione in xenobiotic conjugation and detoxification. Glutathione conjugates xenobiotics to a less reactive form, yielding a mercapturic acid that is excreted by the kidney.

FIG. 8.

The glutathione redox cycle. In the presence of organic hydroperoxides (ROOH), GSH is converted to GSSG, yielding a less reactive product (ROH). GSSG is converted back to GSH by glutathione reductase through an NADPH-dependent reaction.

FIG. 9.

Mechanisms of protein S-glutathionylation. Proteins contain a number of cysteine-sulfhydryl (-SH) residues that may form a disulfide bond with GSH, resulting in protein S-glutathionylation (protein-SSG). “R” represents an organic substituent.

FIG. 10.

Reactive nitrogen species biochemistry. ^•NO is produced from nitric oxide synthases and is then metabolized to the nitric oxide oxidation products nitrite (NO₂⁻) and nitrate (NO₃⁻) through a series of reactions involving superoxide anion (O^•₂⁻) and oxygen. The OONO– that is generated is then protonated to peroxynitrous acid (ONOOH). ONOOH may also react with GSH and other thiol residues to form S-nitrosothiols such as nitrosoglutathione (GSNO). ^•NO, nitric oxide radical

FIG. 11.

Glutathione distribution in the plasma, cell, and epithelial lining fluid of healthy adults. The GSH/GSSG redox potential within the cell varies as a function of differentiation, proliferation/growth arrest, and apoptosis.

FIG. 12.

Hypothesized continuum of glutathione redox disturbances in asthma. Values for GSH and the GSH/GSSG redox potential (E_h) were estimated from existing literature.

FIG. 13.

Consequences of altered GSH/GSSG redox balance in asthma.

FIG. 14.

Role of selenium in glutathione peroxidase activity. The selenol residue (–SeH) of glutathione peroxidase is converted to a selenenic acid in the presence of hydroperoxides (ROOH). GSSG is formed from the reduction of selenenyl sulfide.

FIG. 15.

Role of vitamin B₆ and vitamin B₁₂ in maintaining homeocysteine balance and cysteine availability. Vitamin B₆ is essential for the conversion of homocysteine to cystathionine. Vitamin B₁₂ likewise functions as a cofactor for the re-methylation of homocysteine to methionine.

FIG. 16.

Molecular modulation of airway thiol redox balance and possible role in asthma. In subjects with asthma, decreased airway-reduced GSH reserves may result in a detrimental cascade whereby concentrations of GSSG and oxidized thioredoxin (TRX) are increased and significant post-translational modification of proteins occurs (with excessive oxidation of protein-methionine residues [protein-MetO] and protein disulfide [protein-SS] formation from glutathionylation or other mechanisms). These effects may ultimately overwhelm the functional activities of GPX, glutathione reductases, peroxiredoxins (PRX), thioredoxin reductases, and glutaredoxins (GRX), resulting in insufficient oxidant defenses and characteristic features of asthma.