This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2007-0128OCv1 38/5/509    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lowry, M. H. Articles by Joyce-Brady, M. Search for Related Content PubMed PubMed Citation Articles by Lowry, M. H. Articles by Joyce-Brady, M.

Lung Lining Fluid Glutathione Attenuates IL-13–Induced Asthma

¹ The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts; ² Department of Pediatrics, Emory University, Atlanta, Georgia; ³ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁴ Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts; and ⁵ The Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington

Correspondence and requests for reprints should be addressed to Martin Joyce-Brady, M.D., The Pulmonary Center, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail: mjbrady{at}bu.edu

GGT^enu1 mice, deficient in -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.

Key Words: glutathione • lung lining fluid • asthma

CLINICAL RELEVANCE We identify gamma-glutamyl transferase (GGT) as a target to treat asthma. GGT regulates glutathione metabolism in lung lining fluid. Inhibition of GGT augments lining fluid glutathione, buffers oxidants derived from inflammation, and attenuates asthma.