Reduction of antigen-induced respiratory abnormalities and airway inflammation in sensitized guinea pigs by a superoxide dismutase mimetic.
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.
Masini
Emanuela
E
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. emanuela.masini@unifi.it
Bani
Daniele
D
Vannacci
Alfredo
A
Pierpaoli
Simone
S
Mannaioni
Pier Francesco
PF
Comhair
Suzy A A
SA
Xu
Weiling
W
Muscoli
Carolina
C
Erzurum
Serpil C
SC
Salvemini
Daniela
D
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
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