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.