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Divisions of
*
Immunology and Cell Biology and
Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia
We have used mice rendered deficient for nitric oxide synthase 2
(NOS2) production to study the role of inducible nitric oxide (NO) in
the pathogenesis of allergic airways disease. Using a model with OVA as
aeroallergen, we show that the manifestations of disease, including
infiltration of inflammatory cells, particularly eosinophils, loss of
structural integrity of the airway walls, microvascular leakage,
pulmonary edema, and airway occlusion are markedly less severe in the
NOS2 mutants than in wild-type animals. Indeed, NOS2-deficiency
resulted in a 55–60% reduction in both circulatory and pulmonary
eosinophil numbers following aeroallergen treatment, although
eosinophil maturation or efflux from the bone marrow was not
suppressed. There were no obvious differences in levels of airway
hyperreactivity recorded in OVA-treated wild-type and NOS2-deficient
mice. Interestingly, the suppression of allergic inflammation was
accompanied by marked increases in T cell production of IFN-
but not
by any obvious reduction in the secretion of either IL-4 or IL-5, nor
by major changes in the IgG1 and IgE OVA-specific serum Ig profiles in
the mutants. The markedly enhanced production of IFN- in
NOS2-/- mice was apparently responsible for the
suppression of both eosinophilia and disease, as in vivo depletion of
this factor restored allergic pathology in these animals. Our data
indicate that NOS2 promotes allergic inflammation in airways via
down-regulation of IFN- activity and suggest that inhibitors of this
molecule may represent a worthwhile therapeutic strategy for allergic
diseases including asthma.
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