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We tested the hypothesis that increases in l-ornithine\u2013derived 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.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0323oc","type":"journal-article","created":{"date-parts":[[2013,3,7]],"date-time":"2013-03-07T23:09:42Z","timestamp":1362697782000},"page":"694-702","source":"Crossref","is-referenced-by-count":59,"title":["Increased Ornithine-Derived Polyamines Cause Airway Hyperresponsiveness in a Mouse Model of Asthma"],"prefix":"10.1093","volume":"48","author":[{"given":"Michelle L.","family":"North","sequence":"first","affiliation":[{"name":"Institute of Medical Science, Faculty of Medicine, and"},{"name":"Divisions of Occupational and Respiratory Medicine, Department and Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada"},{"name":"Gage Occupational and Environmental Health Unit, University of Toronto and St. Michael\u2019s Hospital, Toronto, Ontario, Canada"},{"name":"Keenan Research Centre in the Li Ka Shing 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