spl-334 and Bronchial-Hyperreactivity

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.

Topics: Administration, Intranasal; Alcohol Dehydrogenase; Allergens; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bronchial Hyperreactivity; Cell Movement; Chemokine CCL11; Enzyme Inhibitors; Eosinophils; Female; Glutathione Reductase; Humans; Interleukin-13; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Pneumonia; Pyrimidinones; Th2 Cells