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Endogenous S-Nitrosoglutathione Modifies 5-Lipoxygenase Expression in Airway Epithelial Cells

Division of Pulmonary Medicine, Department of Pediatrics, and Department of Surgery, University of Virginia, School of Medicine, and Department of Chemistry, University of Virginia, Charlottesville, Virginia; and Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Correspondence and requests for reprints should be addressed to Dr. Benjamin Gaston, Department of Pediatrics, University of Virginia Health System, P.O. Box 800386, Charlottesville, VA 22908. E-mail: BMG3G{at}virginia.edu

S-Nitrosoglutathione (GSNO) is an endogenous bronchodilator with several beneficial pulmonary effects. Levels are decreased in the asthmatic airway, and GSNO inhalation has been proposed as an asthma therapy. 5-lipoxygenase (5-LO) is the rate-limiting enzyme in the synthetic pathway for cysteinyl leukotrienes (CysLTs), bronchoconstricting agents that are overproduced in asthma. Here, we have studied the effect of GSNO on the expression of 5-LO in human airway A549 cell lines and in primary normal human tracheobronchial epithelial (NHBE) cells in vitro. GSNO at concentrations of 0.5–1 µM caused a 3- to 6-fold increase in 5-LO expression. However, GSNO at > 5 µM significantly inhibited both 5-LO expression and LT production. We also found that airway epithelial cells had -glutamyl transpeptidase (-GT) activity. The effect of 1 µM GSNO on 5-LO expression was prevented by the -GT inhibitor, acivicin, suggesting a convergence of GSNO and CysLT metabolic pathway that may be relevant to asthma. Our data demonstrate that GSNO levels 1 µM, likely recapitulating those in the asthmatic airway, increase 5-LO expression, an effect that may increase inflammation and bronchoconstriction. However, GSNO at concentrations > 5 µM suppresses 5-LO expression. These data suggest that GSNO might inhibit 5-LO expression in the clinical setting.

Key Words: 5-lipoxygenase • asthma • leukotriene • S-nitrosoglutathione • S-nitrosylation