The effects of N-acetylcysteine and glutathione on smoke-induced changes in lung phagocytes and epithelial cells.
We studied the mechanism of the delay in neutrophil traffic in pulmonary microvasculature previously observed during cigarette smoking, the effect of cigarette smoke on lung phagocytes and epithelial cell function, and augmentation of the glutathione (GSH) antioxidant system using the thiol drug N-acetylcysteine. Using a micropore membrane system to mimic the dimensions of the average pulmonary capillary, we showed that cigarette smoke reduces cell deformability, increasing the difficulty experienced by the larger neutrophils in negotiating the smaller capillary segments, so delaying their passage during smoking. This effect is both diminished and recoverable by the addition of plasma, and by GSH in concentrations found in plasma. Cigarette smoke induces oxidative changes in both the cell membrane and the cell cytoskeleton, and diminishes the ability of neutrophils to release reactive oxygen intermediates. The injurious effect of oxidants can be measured in vitro by the detachment of 51Cr-radiolabeled alveolar epithelial cells grown in monolayers, an effect also diminished by the addition of GSH. Such epithelial cell detachment in vitro may be reflected as the epithelial permeability that occurs at an early stage in asymptomatic smokers. N-Acetylcysteine given orally (600 mg/day) increases both plasma and bronchoalveolar lavage GSH in normal subjects, but a sustained increase in plasma GSH requires higher dosage regimens in patients with chronic obstructive pulmonary disease (600 mg three times daily). Thus, the potential exists to enhance the antioxidant status of both plasma and the airspaces of the lungs against oxidant-induced injury.
Department of Medicine, Institute of Occupational Medicine, Edinburgh, Scotland.
W
W
MacNee
M M
MM
Bridgeman
M
M
Marsden
E
E
Drost
S
S
Lannan
C
C
Selby
K
K
Donaldson
D000111:Acetylcysteine / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004848:Epithelium / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000187:drug effects*; D010586:Phagocytes / Q000187:drug effects*; D012907:Smoking / Q000009:adverse effects*
D005978:Glutathione; D000111:Acetylcysteine