Published ahead of print on May 5, 2005, doi:10.1164/rccm.200502-180OC Am. J. Respir. Crit. Care Med., Volume 172, Number 3, August 2005, 306-313 A more recent version of this article appeared on August 1, 2005
Submitted on February 3, 2005 Correlation of Systemic Superoxide Dismutase Deficiency to Airflow Obstruction in AsthmaSuzy A.A. Comhair1*,1 Department of Pathobiology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, 2 Department of Pulmonary, Allergy and Critical Care Medicine, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, 3 Department of Pathobiology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Pulmonary, Allergy and Critical Care Medicine, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, 4 Department of Cell Biology and Center for Cardiovascular Diagnostics and Prevention, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, 5 The Severe Asthma Research Program (SARP), USA * To whom correspondence should be addressed. E-mail: comhais{at}ccf.org.
Rationale: Increased oxidative stress and decreased superoxide dismutase (SOD) activity in the asthmatic airway is 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, glutathione peroxidase/glutathione antioxidant system, and oxidatively modified amino acids were measured in asthmatics and healthy controls. Results: SOD activity, but not MnSOD or CuZnSOD protein, was lower in asthmatic serum as compared to 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 post-translational modification of proteins produced by the eosinophil peroxidase system of eosinophils. Exposure of purified CuZnSOD 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, Antioxidants, GSH
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