title: Reduction of antigen-induced respiratory abnormalities and airway inflammation in sensitized guinea pigs by a superoxide dismutase mimetic.
abstract: Reactive oxygen species have been implicated in the pathogenesis of asthma and, in atopic asthmatics, endogenous superoxide dismutase (SOD) enzyme levels are known to decrease. This suggests that replacing a failed endogenous SOD enzyme system with a mimetic of the endogenous enzyme would be beneficial and protective. In this study we demonstrate that removal of superoxide by the SOD mimetic (SODm) M40403 reduces the respiratory and histopathological lung abnormalities due to ovalbumin (OA) aerosol in a model of allergic asthma-like reaction in sensitized guinea pigs. Both respiratory abnormalities and bronchoconstriction in response to OA challenge are nearly absent in naïve animals, while they sharply became severe in sensitized animals. In addition, OA aerosol induced a reduction of MnSOD activity which was paralleled with bronchiolar lumen reduction, pulmonary air space hyperinflation, mast cell degranulation, eosinophil infiltration, bronchial epithelial cell apoptosis, increase in myeloperoxidase activity, malonyldialdehyde production and 8-hydroxy-2'-deoxyguanosine formation in the lung tissue, as well as elevation of PGD2 in the bronchoalveolar lavage fluid. Treatment with M40403 restored the levels of MnSOD activity and significantly reduced all the above parameters. In summary, our findings support the potential therapeutic use of SOD mimetics in asthma and anaphylactic reactions and account for a critical role for superoxide in acute allergic asthma-like reaction in actively sensitized guinea pig.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. emanuela.masini@unifi.it
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.forename: Alfredo
authors.initials: A
authors.lastname: Vannacci
authors.forename: Simone
authors.initials: S
authors.lastname: Pierpaoli
authors.forename: Pier Francesco
authors.initials: PF
authors.lastname: Mannaioni
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000485:Allergens; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016084:Bronchoconstriction / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008345:Manganese; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010047:Ovalbumin; D009195:Peroxidase / Q000378:metabolism; D015230:Prostaglandin D2 / Q000032:analysis; D013482:Superoxide Dismutase / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000485:Allergens; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D008315:Malondialdehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D010047:Ovalbumin; D009195:Peroxidase; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D015230:Prostaglandin D2