Published ahead of print on December 6, 2007, doi:10.1165/rcmb.2007-0128OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 5, May 2008, 509-516 A more recent version of this article appeared on May 1, 2008
Submitted on April 12, 2007 Lung Lining Fluid Glutathione Attenuates IL-13 Induced AsthmaMatthew H Lowry1,1 The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA, 2 Department of Pediatrics, Emory University, Atlanta, GA, USA, 3 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 4 Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA, USA, 5 The Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA * To whom correspondence should be addressed. E-mail: mjbrady{at}bu.edu.
GGTenu1 mice, deficient in
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-glutamyl transferase and unable to metabolize extracellular glutathione, develop intracellular glutathione deficiency and oxidant stress. We used intratracheal IL13 to induce airway inflammation and asthma in wild type and GGTenu1 mice to determine the effect of altered glutathione metabolism on bronchial asthma. Wild type (WT) and GGTenu1 mice developed similar degrees of lung inflammation. In contrast, IL13 induced airway epithelial cell mucous cell hyperplasia, mucin and mucin-related gene expression, EGFR mRNA, and EGFR activation along with airway hyperreactivity in WT, but not GGTenu1 mice. Lung lining fluid (extracellular) glutathione was 10 fold more in GGTenu1 than WT lungs providing increased buffering of inflammation-associated reactive oxygen species. Pharmacologic inhibition of GGT in WT mice produced similar effects suggesting that 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.