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(American Journal of Pathology. 2005;166:663-674.)
© 2005 American Society for Investigative Pathology

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Suzy A.A. Comhair^*, Weiling Xu^*, Sudakshina Ghosh^*, Frederik B.J.M. Thunnissen, Alexandru Almasan, William J. Calhoun^¶, Allison J. Janocha^*, Lemin Zheng^||, Stanley L. Hazen^||** and Serpil C. Erzurum^*

From the Departments of Pathobiology,^* Pulmonary, Allergy, and Critical Care Medicine, and Cancer Biology, The Lerner Research Institute, the Department of Cell Biology and Center for Cardiovascular Diagnostics and Prevention,|| and the Department of Cardiovascular Medicine,^** The Cleveland Clinic Foundation, Cleveland, Ohio; the Department of Pulmonary Allergy, Critical Care Medicine,^¶ University of Pittsburgh, Pittsburgh, Pennsylvania; and the Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands

Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Furthermore, oxidation and nitration of MnSOD were identified in the asthmatic airway, correlating with physiological parameters of asthma severity. These findings link oxidative and nitrative stress to loss of SOD activity and downstream events that typify asthma, including apoptosis and shedding of the airway epithelium and hyperresponsiveness.

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