PT  - JOURNAL ARTICLE
AU  - Mark A. Birrell
AU  - Kerryn McCluskie
AU  - El-Bdaoui Haddad
AU  - Cliff H. Battram
AU  - Stephen E. Webber
AU  - Martyn L. Foster
AU  - Magdi H. Yacoub
AU  - Maria G. Belvisi
TI  - Pharmacological Assessment of the Nitric-Oxide Synthase Isoform Involved in Eosinophilic Inflammation in a Rat Model of Sephadex-Induced Airway Inflammation
AID  - 10.1124/jpet.102.044339
DP  - 2003 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1285--1291
VI  - 304
IP  - 3
4099  - http://jpet.aspetjournals.org/content/304/3/1285.short
4100  - http://jpet.aspetjournals.org/content/304/3/1285.full
SO  - J Pharmacol Exp Ther2003 Mar 01; 304
AB  - 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 inhibitorl-NAME (NG-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 α, 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. The American Society for Pharmacology and Experimental Therapeutics