This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Severe asthma is poorly understood, is refractory to treatment and causes substantial morbidity and mortality. We have found that the airway redox environment is uniquely abnormal in severe asthma. In this project, we propose to define the role of redox regulation in the pathophysiology of severe asthma. To accomplish this, we will make use of shared resources and patients, new technologies and unique capabilities of investigators at 10 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 activity and an increase in the formation of reactive oxygen species; and 3) Organic and inorganic abnormalities in airway redox regulation in severe asthma decrease levels of beneficial nitrogen oxides (nitric oxide and S-Nitrosothiols) and increase cytotoxic NO reaction products (such as nitrous and peroxynitrous acids) that potentiate airway injury. This study is part of a large multicenter trial of severe asthma, the severe asthma research program (SARP). We have made extensive use of the GCRC through nursing out-patient visits, nitric oxide (NO) measures, pulmonary function testing, methacholine testing, skin allergy testing, all performed through GCRC support. The study has an NIH appointed DSMB, and has a steering committee with international membership.
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