S-nitrosoglutathione reductase inhibition regulates allergen-induced lung inflammation and airway hyperreactivity.

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.

• Authors: Maria E Ferrini, Bryan J Simons, David J P Bassett, Matthews O Bradley, Kevan Roberts, Zeina Jaffar
• Journal: PloS one (PLoS One) Vol. 8 Issue 7 Pg. e70351 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23936192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Anti-Inflammatory Agents, Non-Steroidal
• Benzoates
• Ccl11 protein, mouse
• Chemokine CCL11
• Enzyme Inhibitors
• Interleukin-13
• Interleukin-5
• Pyrimidinones
• SPL-334
• Ovalbumin
• Adh5 protein, mouse
• Alcohol Dehydrogenase
• Glutathione Reductase

Topics

• Administration, Intranasal
• Alcohol Dehydrogenase
• Allergens
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Benzoates (pharmacology)
• Bronchial Hyperreactivity (chemically induced, drug therapy, immunology, pathology)
• Cell Movement (drug effects)
• Chemokine CCL11 (antagonists & inhibitors, biosynthesis)
• Enzyme Inhibitors (pharmacology)
• Eosinophils (drug effects, immunology, pathology)
• Female
• Glutathione Reductase (antagonists & inhibitors, metabolism)
• Humans
• Interleukin-13 (antagonists & inhibitors, biosynthesis)
• Interleukin-5 (antagonists & inhibitors, biosynthesis)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Ovalbumin
• Pneumonia (chemically induced, drug therapy, immunology, pathology)
• Pyrimidinones (pharmacology)
• Th2 Cells (drug effects, immunology, pathology)