title: Role of nitric oxide on eosinophilic lung inflammation in allergic mice.
abstract: Nitric oxide (NO) is an important mediator of inflammatory reactions and may contribute to the lung inflammation in allergic pulmonary diseases. To assess the role of NO in pulmonary inflammation, we studied the effect of four nitric oxide synthase (NOS) inhibitors, N-nitro-L-arginine methyl ester (L-NAME), aminoguanidine, N(G)-monomethyl-L-arginine (NMMA) and L-N6-(1-Iminoethyl) lysine (L-NIL), on the influx of eosinophils into the bronchoalveolar lavage (BAL) fluid and lung tissue of antigen-challenged allergic mice. We also analyzed lung tissues for the presence of steady state mRNA for inducible nitric oxide synthase (iNOS) and iNOS protein. Furthermore, BAL fluid and serum were analyzed for their nitrite content. B6D2F1/J mice were sensitized to ovalbumin (OVA) and challenged with aerosolized OVA. The NOS inhibitors were given 0.5 h before and 4 h after the antigen challenge. OVA challenge induced a marked eosinophilia in the BAL fluid and lung tissue 24 h after challenge. The OVA-induced pulmonary eosinophilia was significantly reduced by L-NAME (10 and 50 mg/kg, intraperitoneally [i.p.]). The inactive isomer, D-NAME (50 mg/kg, i.p.) had no effect. When mice were treated with L-NAME (20 mg/kg, i.p.) and an excess of NOS substrate, L-arginine (200 mg/kg, i.p.), the OVA-induced pulmonary eosinophilia was restored. Treatment with aminoguanidine (0.4-50 mg/kg, i.p.) also reduced the pulmonary eosinophilia. Treatment with NMMA (2-50 mg/kg, i.p.) partially reduced the eosinophilia, but L-NIL (10-50 mg/kg, i.p.), a selective iNOS inhibitor, had no effect. L-NAME had no effect on the reduction of eosinophils in the bone marrow following OVA challenge to sensitized mice. OVA challenge to sensitized mice had no effect on iNOS protein expression or iNOS mRNA in the lungs or on the levels of nitrite in the BAL fluid. These results suggest that NO is involved in the development of pulmonary eosinophilia in allergic mice. The NO contributing to the eosinophilia is not generated through the activity of iNOS nor does NO contribute to the efflux of eosinophils from the bone marrow in response to antigen challenge. It is speculated that after antigen challenge, the localized production of NO, possibly from pulmonary vascular endothelial cells, is involved in the extravasation of eosinophils from the circulation into the lung tissue.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Feder
authors.forename: D
authors.initials: D
authors.lastname: Stelts
authors.forename: R W
authors.initials: RW
authors.lastname: Chapman
authors.forename: D
authors.initials: D
authors.lastname: Manfra
authors.forename: Y
authors.initials: Y
authors.lastname: Crawley
authors.forename: H
authors.initials: H
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Minnicozzi
authors.forename: X
authors.initials: X
authors.lastname: Fernandez
authors.forename: T
authors.initials: T
authors.lastname: Paster
authors.forename: R W
authors.initials: RW
authors.lastname: Egan
authors.forename: W
authors.initials: W
authors.lastname: Kreutner
authors.forename: T T
authors.initials: TT
authors.lastname: Kung
mesh_terms: D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase