Abstract
Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4(+) Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intranasal
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Alcohol Dehydrogenase
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Allergens
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Benzoates / pharmacology*
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Bronchial Hyperreactivity / chemically induced
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Bronchial Hyperreactivity / drug therapy*
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Bronchial Hyperreactivity / immunology
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Bronchial Hyperreactivity / pathology
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Cell Movement / drug effects
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Chemokine CCL11 / antagonists & inhibitors
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Chemokine CCL11 / biosynthesis
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Enzyme Inhibitors / pharmacology*
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Eosinophils / drug effects
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Eosinophils / immunology
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Eosinophils / pathology
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Female
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Glutathione Reductase / antagonists & inhibitors*
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Glutathione Reductase / metabolism
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Humans
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Interleukin-13 / antagonists & inhibitors
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Interleukin-13 / biosynthesis
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Interleukin-5 / antagonists & inhibitors
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Interleukin-5 / biosynthesis
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Ovalbumin
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Pneumonia / chemically induced
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Pneumonia / drug therapy*
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Pneumonia / immunology
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Pneumonia / pathology
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Pyrimidinones / pharmacology*
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Th2 Cells / drug effects
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Th2 Cells / immunology
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Th2 Cells / pathology
Substances
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Allergens
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Anti-Inflammatory Agents, Non-Steroidal
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Benzoates
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Ccl11 protein, mouse
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Chemokine CCL11
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Enzyme Inhibitors
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Interleukin-13
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Interleukin-5
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Pyrimidinones
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SPL-334
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Ovalbumin
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Adh5 protein, mouse
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Alcohol Dehydrogenase
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Glutathione Reductase