Endogenous S-nitrosoglutathione modifies 5-lipoxygenase expression in airway epithelial cells.
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 microM caused a 3- to 6-fold increase in 5-LO expression. However, GSNO at>5 microM significantly inhibited both 5-LO expression and LT production. We also found that airway epithelial cells had gamma-glutamyl transpeptidase (gamma-GT) activity. The effect of 1 microM GSNO on 5-LO expression was prevented by the gamma-GT inhibitor, acivicin, suggesting a convergence of GSNO and CysLT metabolic pathway that may be relevant to asthma. Our data demonstrate that GSNO levels<or=1 microM, likely recapitulating those in the asthmatic airway, increase 5-LO expression, an effect that may increase inflammation and bronchoconstriction. However, GSNO at concentrations>5microM suppresses 5-LO expression. These data suggest that GSNO might inhibit 5-LO expression in the clinical setting.
Zaman
Khalequz
K
Department of Pediatrics, University of Virginia Health System, P.O. Box 800386, Charlottesville, VA 22908, USA.
Hanigan
Marie H
MH
Smith
Alison
A
Vaughan
John
J
Macdonald
Timothy
T
Jones
David R
DR
Hunt
John F
JF
Gaston
Benjamin
B
D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis*; D001993:Bronchodilator Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020030:Nitric Oxide Donors / Q000494:pharmacology; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology*; D026422:S-Nitrosoglutathione / Q000378:metabolism* / Q000494:pharmacology; D016329:Sp1 Transcription Factor / Q000502:physiology; D051705:Sp3 Transcription Factor / Q000502:physiology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
D001993:Bronchodilator Agents; D020030:Nitric Oxide Donors; D016329:Sp1 Transcription Factor; C497123:Sp3 protein, rat; D051705:Sp3 Transcription Factor; D026422:S-Nitrosoglutathione; C066851:mithramycin A; D001094:Arachidonate 5-Lipoxygenase; D005723:gamma-Glutamyltransferase; D046988:Proteasome Endopeptidase Complex; D008926:Plicamycin