Lung Lining Fluid Glutathione Attenuates IL-13-Induced Asthma

GGT(enu1) mice, deficient in gamma-glutamyl transferase and unable to metabolize extracellular glutathione, develop intracellular glutathione deficiency and oxidant stress. We used intratracheal IL-13 to induce airway inflammation and asthma in wild-type (WT) and GGT(enu1) mice to determine the effect of altered glutathione metabolism on bronchial asthma. WT and GGT(enu1) mice developed similar degrees of lung inflammation. In contrast, IL-13 induced airway epithelial cell mucous cell hyperplasia, mucin and mucin-related gene expression, epidermal growth factor receptor mRNA, and epidermal growth factor receptor activation along with airway hyperreactivity in WT mice but not in GGT(enu1) mice. Lung lining fluid (extracellular) glutathione was 10-fold greater in GGT(enu1) than in WT lungs, providing increased buffering of inflammation-associated reactive oxygen species. Pharmacologic inhibition of GGT in WT mice produced similar effects, suggesting that the lung lining fluid glutathione protects against epithelial cell induction of asthma. Inhibiting GGT activity in lung lining fluid may represent a novel therapeutic approach for preventing and treating asthma.