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*
Novartis Horsham Research Centre, Horsham, United Kingdom;
Immuno-Hematology Group, Hôpital La Pitié Salpêtrière, Paris, France; and
Roche Bioscience, Palo Alto, CA
Growing evidence demonstrates that inducible NO synthase (iNOS) is
induced in the airways of asthmatic patients. However, the precise role
of NO in the lung inflammation is unknown. This study investigated the
effect of both selective and nonselective iNOS inhibitors in an
allergen-driven murine lung inflammation model. OVA challenge resulted
in an accumulation of eosinophils and neutrophils in the airways.
Expression of iNOS immunostaining in lung sections together with an
increase in calcium-independent NOS activity in lung homogenates was
also observed after OVA challenge. Treatment with iNOS inhibitors from
the day of challenge to the day of sacrifice resulted in an inhibition
of the inflammatory cell influx together with a down-regulation of
macrophage inflammatory protein-2 and monocyte chemoattractant
protein-1 production. In contrast, eosinophilic and neutrophilic
inhibition was not observed with treatment during the sensitization.
Both treatments induced an increased production of Th2-type cytokines
(IL-4 and IL-5) with a concomitant decrease in production of Th1-type
cytokine (IFN-
). In vitro exposure of primary cultures of murine
lung fibroblasts to a NO donor, hydroxylamine, induced a dose-dependent
release of macrophage inflammatory protein-2 and monocyte
chemoattractant protein-1. Our results suggest that lung inflammation
after allergen challenge in mice is partially dependent on NO produced
mainly by iNOS. NO appears to increase lung chemokine expression and,
thereby, to facilitate influx of inflammatory cells into the
airways.
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