Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis

Abstract

Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils and macrophages on the respiratory epithelial surface (RES); these cells release toxic oxidants, which contribute to the marked epithelial derangements seen in CF. These deleterious consequences are magnified, since reduced glutathione (GSH), an antioxidant present in high concentrations in normal respiratory epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the feasibility of increasing ELF GSH levels and enhancing RES antioxidant protection, GSH aerosol was delivered (600 mg twice daily for 3 days) to seven patients with CF. ELF total, reduced, and oxidized GSH increased (P < 0.05, all compared with before GSH therapy), suggesting adequate RES delivery and utilization of GSH. Phorbol 12-myristate 13-acetate-stimulated superoxide anion (O2-.) release by ELF inflammatory cells decreased after GSH therapy (P < 0.002). This paralleled observations that GSH added in vitro to CF ELF inflammatory cells suppressed O2-. release (P < 0.001). No adverse effects were noted during treatment. Together, these observations demonstrate the feasibility of using GSH aerosol to restore RES oxidant-antioxidant balance in CF and support the rationale for further clinical evaluation.

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

“…GSH inhalation could therefore be associated with undesired effects: oxidized glutathione (GSSG) could affect cellular receptor and signaling activities by inducing changes in protein structure and function via effects on redox-active protein thiol groups [82]. Furthermore, the inflammatory cells recovered in the BALF in this study produced less superoxide anions than before therapy, suggesting the GSH treatment could potentially compromise airway antimicrobial host defenses [83]. Preliminary trials of inhaled GSH have shown no significant adverse clinical events in either healthy subjects or individuals with CF [84,85], although the number of subjects in these studies was small.…”

Oxidative stress and regulation of glutathione in lung inflammation

“…Thus increasing lung cellular levels of the GSH/ antioxidant screen would be a logical approach in inflammatory lung diseases. Extracellular augmentation of GSH has been attempted through intravenous administration of GSH, oral ingestion of GSH and inhalation of nebulized GSH [252±260] in an attempt to reduce inflammation in lung diseases [261] such as in IPF [253], mild asthmatics [254] and CF [255,256]. GSH aerosol therapy normalized low GSH levels in the lungs of these patients [253±256]; however, nebulized GSH also had a detrimental effect in asthmatic patients by producing bronchoconstriction, presumably due to the formation of GSSG [254].…”

“…The depletion of lung GSH may be reflected in peripheral blood lymphocytes in these patients [144]. It may be feasible to use a GSH aerosol to restore the oxidant/ antioxidant imbalance in these patients [256,259]. In all of these studies, questions were raised as to the bioavailability of GSH, the pH and osmolality at the site of the microenvironment and the resultant formation of deleterious products (GSSG).…”

Oxidative stress in cystic fibrosis lung disease: an early event, but worth targeting?

“…Several attempts to deliver glutathione into CF airways were capable of delivering substantial amounts of glutathione [18,19,21] and demonstrated reduced superoxide anion formation by inflammatory cells [21], as well as modulation of pulmonary immune responses [22]. However, parameters of oxidative stress (myeloperoxidase, ascorbic acid, uric acid and others) were not significantly affected in these studies [18,19,22].…”