S-nitrosoglutathione reductase inhibition regulates allergen-induced lung inflammation and airway 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.
Center for Environmental Health Sciences, Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, Montana, United States of America.
Maria E
ME
Ferrini
Bryan J
BJ
Simons
David J P
DJ
Bassett
Matthews O
MO
Bradley
Kevan
K
Roberts
Zeina
Z
Jaffar
D000281:Administration, Intranasal; D000426:Alcohol Dehydrogenase; D000485:Allergens; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011744:Pyrimidinones / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D004791:Enzyme Inhibitors; D018793:Interleukin-13; D015848:Interleukin-5; D011744:Pyrimidinones; C000602674:SPL-334; D010047:Ovalbumin; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D005980:Glutathione Reductase