Commentary SOD Inactivation in Asthma Bad News or NO News

Changes in the oxidative milieu are well known to accompany inflammatory diseases, including asthma, and the severity of oxidative stress, measured through the accumulation of stable oxidation end products, often directly correlates with the severity of disease. As an example, tyrosine nitration has been reported to positively associate with cardiac disease, and a direct correlation between nitrotyrosine reactivity and functional abnormalities has been reported in patients with asthma. These observations, coupled with animal studies demonstrating that administration of antioxidant compounds ameliorate various manifestations of inflammatory disorders and that transgenic mice overexpressing antioxidant enzymes display attenuated damage, have provided substantial evidence in support of a causal role of oxidative changes in the inflammatory disease process. Nonetheless, a mechanistic basis underlying such causality is generally lacking, due to an overall failure to pinpoint the critical oxidative targets in relation to functional changes that drive the disease process. In this regard, the study by Dr. Comhair and colleagues in this issue of The American Journal of Pathology has made significant progress in delineating critical oxidative events in patients with asthma and the role these oxidative alterations may play in the morphological and functional alterations seen in the asthmatic lung. The authors demonstrate in bronchial brush material obtained from patients with mild asthma that SOD is inactivated. Using sophisticated mass spectrometric analyses and immuno-approaches, they also reveal that the mitochondrially localized isoform of superoxide dismutase (SOD), MnSOD, contains multiple oxidations of phenylalanines and tyrosines, including nitrated tyrosine residues. To address the ramifications of such oxidative inactivation of MnSOD, the authors used a chemical inhibitor of SOD in a human bronchial epithelial cell line, or knocked down MnSOD using siRNA, and demonstrated that SOD inactivation or knockdown is sufficient to cause apoptosis. These results are consistent with their observations in epithelial brushings from patients which also revealed evidence of apoptosis, as evidenced by increases in TUNEL reactivity, caspase 3 and 9 cleavage and activation, and PARP cleavage. Lastly, decreases in SOD activity in asthmatics were found to correlate with decreased lung function. Thus, the scenario emerges that oxidative inactivation of SOD within cells of the conducting airways leads to enhanced apoptosis and a compromised epithelial barrier. These are considered potential contributors to airway hyper responsiveness in patients with asthma and can also fuel airway remodeling. These findings are highly significant in that they not only highlight the strength of translational studies but also provide a much needed mechanistic framework toward elucidating the mechanism of action of oxidants in the pulmonary inflammatory disease process. Despite the importance of the present study by Comhair et al in providing evidence for mechanistic links between specific oxidative events, changes in antioxidant function, and decreased epithelial integrity or lung function, a number of unresolved questions remain that will provide a continued challenge for future investigations. First, it remains unclear to what extent the measured tyrosine modifications within MnSOD from samples of asthmatic patients actually contribute to inactivation of the enzyme and consequently drive the apoptotic process. While the efforts to relate changes in SOD activity to specific oxidative modifications are highly commendable, especially considering the challenges associated with analysis of patient specimens, only selected oxida-