Severe asthma is poorly understood, is refractory to treatment and causes substantial morbidity and mortality. The airway redox environment is uniquely abnormal in severe asthma. In particular, our work has revealed: (1) impaired regulation of airway acidity because of decreased expression and activity of airway epithelial glutaminase; (2) an oxidizing airway environment with loss of antioxidant Cu/Zn superoxide dismutase activity; (3) decreased nitric oxide, when compared to mild asthma, in part because of increased consumption by superoxide and generation of toxic reactive nitrogen species; and (4) subsequent decrease of beneficial bronchodilator S-Nitrosothiols due to accelerated catabolism in the oxidative and acidic airway. In this proposal, we propose to define the role of airway pH, reducing and oxidizing events in the pathophysiology of severe asthma through the use of shared resources and patients, new technologies and unique capabilities of investigators at three large asthma centers. We propose to test the following hypotheses: 1. airway epithelial glutaminase activity is decreased in severe asthma, resulting in decreased ammonia production and impaired regulation of airway pH; 2. The airway environment in severe asthma is oxidizing because of loss of superoxide dismutase (SOD) activity and increase in reactive oxygen species; and 3. Organic and inorganic abnormalities in airway redox regulation in severe asthma decrease levels of beneficial nitrogen oxides (NO and SNO) and increase cytotoxic NO reaction products (HNO2 and ONOO-) that potentiate airway injury. We predict that severe asthma is related to abnormalities in airway redox chemistry, and that markers for these abnormalities will be correlated to severity of (1) asthma symptoms (by category); (2) airway reactivity; and (3) regional ventilation abnormality as assessed by a novel asthma imaging technology, hyperpolarized helium magnetic resonance imaging.
The specific aims address these hypotheses and, each is designed to have the potential to lead to new, specific, therapies for severe asthma.
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