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Correlation of Systemic Superoxide Dismutase Deficiency to Airflow Obstruction in Asthma

Suzy A. A. Comhair, Kristin S. Ricci, Mercedes Arroliga, Abigail R. Lara, Raed A. Dweik, Wei Song, Stanley L. Hazen, Eugene R. Bleecker, William W. Busse, Kian Fan Chung, Benjamin Gaston, Annette Hastie, Mark Hew, Nizar Jarjour, Wendy Moore, Stephen Peters, W. Gerald Teague, Sally E. Wenzel, Serpil C. Erzurum for the Severe Asthma Research Program of the National Heart, Lung, and Blood Institute

Departments of Pathobiology, Pulmonary, Allergy, and Critical Care Medicine, and Cell Biology, and Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Suzy A. A. Comhair, Ph.D., Cleveland Clinic Foundation, 9500 Euclid Avenue/NB40, Cleveland, OH 44195. E-mail: comhais{at}ccf.org

Rationale: Increased oxidative stress and decreased superoxide dismutase (SOD) activity in the asthmatic airway are correlated to airflow limitation and hyperreactivity. We hypothesized that asthmatic individuals with higher levels of oxidative stress may have greater loss of SOD activity, which would be reflected systemically in loss of circulating SOD activity and clinically by development of severe asthma and/or worsening airflow limitation. Methods: To investigate this, serum SOD activity and proteins, the glutathione peroxidase/glutathione antioxidant system, and oxidatively modified amino acids were measured in subjects with asthma and healthy control subjects. Results: SOD activity, but not Mn-SOD or Cu,Zn-SOD protein, was lower in asthmatic serum as compared with control, and activity loss was significantly related to airflow limitation. Further, serum SOD activity demonstrated an inverse correlation with circulating levels of 3-bromotyrosine, a posttranslational modification of proteins produced by the eosinophil peroxidase system of eosinophils. Exposure of purified Cu,Zn-SOD to physiologically relevant levels of eosinophil peroxidase-generated reactive brominating species, reactive nitrogen species, or tyrosyl radicals in vitro confirmed that eosinophil-derived oxidative pathways promote enzyme inactivation. Conclusion: These findings are consistent with greater oxidant stress in asthma leading to greater inactivation of SOD, which likely amplifies inflammation and progressive airflow obstruction.

Key Words: asthma • superoxide dismutase • glutathione • pulmonary functions • peroxidase

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