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1 INSERM U408, Institut National de la Sante et de la Recherde Medicale, Paris, France
2 Leukocyte Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London, United Kingdom
3 Service de Biochimie, Hopital Kremlin-Bicetre, Universite Paris Sud, Le Kremlin Bicetre, Paris, France
4 Service d'Anatomie Pathologique, Hopital Bichat, Paris, France
* To whom correspondence should be addressed. E-mail: jbb2{at}bichat.inserm.fr.
Heme oxygenase (HO), the heme-degrading enzyme, has shown anti-inflammatory effects in several models of pulmonary diseases. HO is induced in airways during asthma; however its functional role is unclear. Therefore, we evaluated the role of HO on airway inflammation (evaluated by bronchoalveolar lavage -BAL- cellularity, and BAL levels of eotaxin, PGE2 and proteins), mucus secretion (evaluated by analysis of MUC5AC gene expression and PAS staining), oxidative stress (evaluated by quantification of 4-hydroxynonenal adducts and carbonylated protein levels in lung homogenates) and airway responsiveness to histamine in ovalbumin (OVA)-sensitized and multiple aerosol OVA or saline-challenged guinea pigs (6 challenges, once daily, groups OVA and C respectively). Airway inflammation, mucus secretion, oxidative stress and responsiveness were significantly increased in group OVA as compared to group C. HO up-regulation by repeated administrations of hemin (50 mg/kg, intraperitoneally) significantly decreased airway responsiveness in C animals and airway inflammation, mucus secretion, oxidative stress and responsiveness in OVA animals. These effects were reversed by the concomitatnt administration of the HO inhibitor tin protoporphyrin-IX (50 µmol/kg, intraperitoneally). Repeated administrations of tin protoporphyrin-IX alone significantly increased airway responsiveness in C animals, but did not modify airway inflammation, mucus secretion, oxidative stress and responsiveness in OVA animals. These results suggest that up-regulation of the HO pathway has a significant protective effect against airway inflammation, mucus hypersecretion, oxidative stress and hyperresponsiveness in a model of allergic asthma in guinea pigs.
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