title: Inducible nitric oxide synthase inhibitors suppress airway inflammation in mice through down-regulation of chemokine expression.
abstract: Growing evidence demonstrates that inducible NO synthase (iNOS) is induced in the airways of asthmatic patients. However, the precise role of NO in the lung inflammation is unknown. This study investigated the effect of both selective and nonselective iNOS inhibitors in an allergen-driven murine lung inflammation model. OVA challenge resulted in an accumulation of eosinophils and neutrophils in the airways. Expression of iNOS immunostaining in lung sections together with an increase in calcium-independent NOS activity in lung homogenates was also observed after OVA challenge. Treatment with iNOS inhibitors from the day of challenge to the day of sacrifice resulted in an inhibition of the inflammatory cell influx together with a down-regulation of macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 production. In contrast, eosinophilic and neutrophilic inhibition was not observed with treatment during the sensitization. Both treatments induced an increased production of Th2-type cytokines (IL-4 and IL-5) with a concomitant decrease in production of Th1-type cytokine (IFN-gamma). In vitro exposure of primary cultures of murine lung fibroblasts to a NO donor, hydroxylamine, induced a dose-dependent release of macrophage inflammatory protein-2 and monocyte chemoattractant protein-1. Our results suggest that lung inflammation after allergen challenge in mice is partially dependent on NO produced mainly by iNOS. NO appears to increase lung chemokine expression and, thereby, to facilitate influx of inflammatory cells into the airways.
authors.affiliation: Novartis Horsham Research Centre, Horsham, United Kingdom; Immuno-Hematology Group, Hôpital La Pitié Salpêtrière, Paris, France. alexandra.trifilieff@pharma.novartis.com
authors.forename: A
authors.initials: A
authors.lastname: Trifilieff
authors.forename: Y
authors.initials: Y
authors.lastname: Fujitani
authors.forename: F
authors.initials: F
authors.lastname: Mentz
authors.forename: B
authors.initials: B
authors.lastname: Dugas
authors.forename: M
authors.initials: M
authors.lastname: Fuentes
authors.forename: C
authors.initials: C
authors.lastname: Bertrand
mesh_terms: D000281:Administration, Intranasal; D000336:Aerosols; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002021:Buffers; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019811:Hydroxylamine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012965:Sodium Chloride / Q000008:administration & dosage / Q000276:immunology; D013843:Thiazines / Q000008:administration & dosage
chemical_list: C093124:2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine; D000336:Aerosols; D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D018925:Chemokines; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D013843:Thiazines; D019811:Hydroxylamine; D012965:Sodium Chloride; D010047:Ovalbumin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester