Lung Lining Fluid Glutathione Attenuates IL-13–Induced Asthma

Abstract

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.

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

“…A significant increase in versican accumulation occurs in the interstitial space of small and large airways of patients with asthma (11-13, 15, 46) and in animal models of asthma (17,18). Cells isolated from diseased lungs also exhibit altered versican production.…”

Human GGT2 Does Not Autocleave into a Functional Enzyme: A Cautionary Tale for Interpretation of Microarray Data on Redox Signaling

“…It is induced in many tumors, contributing to their resistance to alkylating agents and other classes of chemotherapeutic drugs (15,16). GGT1 is also implicated in asthma, cardiovascular disease, and diabetes (12,30,44).…”

Antioxidant Strategies in the Treatment of Bronchial Asthma

“…Cellular antioxidants, such as glutathione, can affect the redox milieu of immune cells to attenuate pro-inflammatory cytokine induction (12). Extracellular antioxidants, such as lung lining fluid (LLF) glutathione, can buffer reactive oxygen species (ROS) from inflammatory cells, protect airway epithelial cells against oxidant stress and prevent airway hyperreactivity (14).…”

“…They supported epidemiologic studies that linked antioxidant intake with decreased risk of asthma severity 30,31 , and reinvigorated a search for antioxidant therapeutics to treat asthma despite the fact that single antioxidant agents were largely ineffective in clinical trials. In adition, studies using a mouse model of impaired glutathione metabolism together with those using glutathione precursors to manipulate glutathione homeostasis raised the possibility that antioxidants from separate intracellular or extracellular pools may be relevant for different cell types during asthma pathogenesis, such as immune cells during sensitization and epithelial cells in response to inflammation 12,14 .…”

“…Examples of this include glutathione selective approaches to augment content in extracellular pools by targeting glutathione metabolism in lung lining fluid 14,34 or intracellular pools using glutathione precursors 12 . Other approaches that have been suggested include mitochondria-targeted antioxidants 6 or synthetic catalytic ROS scavengers 35,36 that can gain intracellular access, in some cases mitochondrial access 37,38 .…”