Increased glutaredoxin-1 and decreased proteinS-glutathionylation in sputum of asthmatics

Abstract

To the Editor: Total reduced glutathione (GSH), the main pulmonary antioxidant, is increased in asthma patients and, in some studies, increased amounts of oxidised glutathione (GSSG) were also found. In addition, enzymes that regulate the GSH redox cycle are altered in asthmatics (reviewed in [1]). GSH, with its redox cycle partners, serves to maintain the reduced state of protein thiols, which can be achieved by scavenging oxidants or by the covalent reversible binding of GSH to protein thiols. The latter occurs under physiological conditions, is induced upon mild oxidative stress and is known as S -glutathionylation (PSSG) [2]. PSSG protects targeted thiols from irreversible oxidations and can modulate protein function. Of significant relevance in asthma, SERCA (sarco/endoplasmic reticulum calcium ATPase) is activated by PSSG, increasing smooth muscle relaxation, and PSSG of the RyR (ryanodine receptor) calcium channel was associated with impaired coupling. With respect to inflammation, nuclear factor-κB and activator protein-1 are negatively affected by PSSG (reviewed in [2]). GSH can be removed from proteins by glutaredoxins (Grx), which restores the function of proteins targeted by PSSG [2]. The Grx1 isoform localises to the cytosol, and Grx2 to mitochondria and the nucleus. Grx1 can also reduce low molecular weight disulfides and, thus, proteins with functionally important disulfide bonds could also be affected by Grx1 alterations. In contrast to damaging oxidations and measurements of GSH, PSSG and Grx have rarely been studied in lung diseases, and never in conjunction. In chronic obstructive pulmonary disease (COPD), Grx1-positive alveolar macrophages were negatively correlated with forced expiratory volume in 1 s (FEV1) and sputum Grx1 levels were higher during exacerbations [3]. In a murine model of allergic airway disease, we found increased Grx1 expression and activity [4]. Given the importance of …