Airway Thiol-NO Adducts as Determinants of Exhaled NO

Thiol-NO adducts such as S-nitrosoglutathione (GSNO) are endogenous bronchodilators in human airways. Decreased airway S-nitrosothiol concentrations are associated with asthma. Nitric oxide (NO), a breakdown product of GSNO, is measured in exhaled breath as a biomarker in asthma; an elevated fraction of expired NO (F-ENO) is associated with asthmatic airway inflammation. We hypothesized that F-ENO could reflect airway S-nitrosothiol concentrations. To test this hypothesis, we first studied the relationship between mixed expired NO and airway S-nitrosothiols in patients endotracheally intubated for respiratory failure. The inverse (Lineweaver-Burke type) relationship suggested that expired NO could reflect the rate of pulmonary S-nitrosothiol breakdown. We thus studied NO evolution from the lungs of mice (GSNO reductase (-/-)) unable reductively to catabolize GSNO. More NO was produced from GSNO in the (-/-) compared to wild type lungs. Finally, we formally tested the hypothesis that airway GSNO increases F-ENO using an inhalational challenge model in normal human subjects. F-ENO increased in all subjects tested, with a median t(1/2) of 32.0 min. Taken together, these data demonstrate that F-ENO reports, at least in part, GSNO breakdown in the lungs. Unlike GSNO, NO is not present in the lungs in physiologically relevant concentrations. However, F-ENO following a GSNO challenge could be a non-invasive test for airway GSNO catabolism.