Improvement of Alveolar Glutathione and Lung Function but Not Oxidative State in Cystic Fibrosis

Abstract

Chronic neutrophilic inflammation leads to oxidative damage, which may play an important role in the pathogenesis of cystic fibrosis lung disease. Bronchoalveolar lavage levels of the antioxidant glutathione are diminished in patients with cystic fibrosis. Here we evaluated the effects of glutathione aerosol on lower airway glutathione levels, lung function, and oxidative status. Pulmonary deposition of a radiolabeled monodisperse aerosol generated with a Pari LC Star nebulizer (Allergy Asthma Technology, Morton Grove, IL) connected to an AKITA inhalation device (Inamed, Gauting, Germany) was determined in six patients. In 17 additional patients bronchoalveolar lavage fluid was assessed before and after 14 days of inhalation with thrice-daily doses of 300 or 450 mg of glutathione. Intrathoracic deposition was 86.3 +/- 1.4% of the emitted dose. Glutathione concentration in lavage 1 hour postinhalation was increased three- to fourfold and was still almost doubled 12 hours postinhalation. FEV(1) transiently dropped after inhalation but increased compared with pretreatment values after 14 days (p < 0.001). This improvement was not related to the lavage content of oxidized proteins and lipids, which did not change with treatment. These results show that, using a new inhalation device with high efficacy, glutathione treatment of the lower airways is feasible. Reversion of markers of oxidative injury may need longer treatment, higher doses, or different types of antioxidants.

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

“…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.…”

“…More rigorous testing was performed in a trial of inhaled GSH that examined the intrapulmonary deposition of the drug and assessed the tolerance and short-term effects of an optimized inhalation system (AKITA inhalation device, connected to a Pari LC Star nebulizer) [84]. Tests using inhaled 99m Tc-labeled Fe 3 O 4 aerosol particles in 6 subjects aged 35±2 years, with an average FEV 1 of 69.6±7% (range 50-99%) demonstrated that the majority of material was deposited in the peripheral airways with a small fraction in the central airways.…”

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

“…Our data also suggest that systemic therapies that increase epithelial cell GSH production could be of benefit to patients with CF with a mild CFTR genotype. For patients with CF with a severe CFTR genotype, our results suggest that systemic therapies that increase epithelial cell GSH levels may not be as beneficial, although inhaled therapy may be a more appropriate method of increasing GSH levels in the ELF of these patients (50).…”

Aerosolized Medications for Gene and Peptide Therapy

“…Normally, glutathione concentration in the epithelial lining fluid of the lungs is high, [111][112][113] but is depleted in CF. [112][113][114] Early studies investigated whether glutathione inhalation could improve glutathione levels in the lungs. One study showed improvement in alveolar glutathione levels and lung function in subjects with CF after inhalation of glutathione, but no antioxidant effects.…”