Up-regulation of
arginase contributes to airways hyperresponsiveness (AHR) in
asthma by reducing
L-arginine bioavailability for the
nitric oxide (
NO) synthase isozymes. The product of
arginase activity, L-
ornithine, can be metabolized into
polyamines by
ornithine decarboxylase. We tested the hypothesis that increases in L-
ornithine-derived
polyamines contribute to AHR in mouse models of allergic airways
inflammation. After measuring significantly increased
polyamine levels in sputum samples from human subjects with
asthma after
allergen challenge, we used acute and subacute
ovalbumin sensitization and challenge mouse models of allergic airways
inflammation and naive mice to investigate the relationship of AHR to
methacholine and
polyamines in the lung. We found that
spermine levels were elevated significantly in lungs from the acute model, which exhibits robust AHR, but not in the subacute murine model of
asthma, which does not develop AHR. Intratracheal administration of
spermine significantly augmented airways responsiveness to
methacholine in both naive mice and mice with subacute airways
inflammation, and reduced
nitrite/
nitrate levels in lung homogenates, suggesting that the AHR developed as a consequence of inhibition of constitutive NO production in the airways. Chronic inhibition of
polyamine synthesis using an
ornithine decarboxylase inhibitor significantly reduced
polyamine levels, restored
nitrite/
nitrate levels to normal, and abrogated the AHR to
methacholine in the acute model of allergic airways
inflammation. We demonstrate that
spermine increases airways responsiveness to
methacholine, likely through inhibition of constitutive NO synthesis. Thus, inhibition of
polyamine production may represent a new therapeutic target to treat
airway obstruction in allergic
asthma.