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Pharmacological assessment of the nitric-oxide synthase isoform involved in eosinophilic inflammation in a rat model of sephadex-induced airway inflammation.

Authors: Birrell, MA  McCluskie, K  Haddad el-B, I  Battram, CH  Webber, SE  Foster, ML  Yacoub, MH  Belvisi, MG 
Citation: Birrell MA, etal., J Pharmacol Exp Ther. 2003 Mar;304(3):1285-91.
Pubmed: (View Article at PubMed) PMID:12604708
DOI: Full-text: DOI:10.1124/jpet.102.044339

Excessive local production of nitric oxide (NO) has been suggested to play a role in rodent models of airway inflammation and in pulmonary diseases such as asthma. However, even given the plethora of data available including gene expression data, pharmacological data, and gene deletion studies in animal models, it is still not clear which nitric-oxide synthase (NOS) isoform is involved in eosinophilic airway inflammation. In this rat study, the nonselective NOS inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester), but not a selective inducible NOS (iNOS) inhibitor 1400W (N-3-(aminomethyl)benzyl)acetamidine), impacted on Sephadex-induced inflammation by significantly inhibiting lung edema, eosinophil infiltration, tumor necrosis factor alpha, interleukin-13, and eotaxin levels in the lung tissue. Furthermore, iNOS gene expression was not induced following Sephadex administration, which confirms that iNOS does not play a role in this model. To demonstrate that this phenomenon was not restricted to this model of asthma, L-NAME, but not 1400W, was shown to reduce eosinophilia in an antigen-induced model. However, in contrast to the Sephadex model, there was an induction of iNOS gene expression after antigen challenge. In a model of aerosolized lipopolysaccharide-induced inflammation, where iNOS gene expression is increased, 1400W inhibited the increased neutrophilia. These data suggest that the compound has been administered using an appropriate dosing regimen for iNOS inhibition in the rat lung. In conclusion, it appears that constitutive, not inducible, NOS isoforms are important in NO production in models of allergic inflammation, which questions whether there is a role for iNOS inhibitors as therapy for the treatment of asthma.

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CRRD Object Information
CRRD ID: 2301686
Created: 2008-10-28
Species: All species
Last Modified: 2008-10-28
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.