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Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2013 Jun; Vol. 48 (6), pp. 694-702. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Adolescent
Adult
Animals
Asthma drug therapy
Asthma immunology
Asthma metabolism
Disease Models, Animal
Eflornithine pharmacology
Female
Humans
Hypersensitivity drug therapy
Hypersensitivity immunology
Hypersensitivity metabolism
Inflammation immunology
Inflammation metabolism
Inflammation pathology
Lung drug effects
Lung immunology
Lung metabolism
Lung pathology
Male
Methacholine Chloride metabolism
Methacholine Chloride pharmacology
Mice
Middle Aged
Nitrates metabolism
Nitric Oxide metabolism
Nitric Oxide Synthase immunology
Nitric Oxide Synthase metabolism
Ornithine Decarboxylase metabolism
Ornithine Decarboxylase Inhibitors
Ovalbumin adverse effects
Ovalbumin immunology
Polyamines antagonists & inhibitors
Spermine administration & dosage
Spermine adverse effects
Spermine pharmacology
Sputum metabolism
Young Adult
Asthma pathology
Hypersensitivity pathology
Ornithine metabolism
Polyamines metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 48
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 23470627
- Full Text :
- https://doi.org/10.1165/rcmb.2012-0323OC