Browsing by Subject "S-nitrosoglutathione"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Airway Thiol-NO Adducts as Determinants of Exhaled NO
    (MDPI, 2021-09-26) Pophal, Megan; Grimmett, Zachary W.; Chu, Clara; Margevicius, Seunghee; Raffay, Thomas; Ross, Kristie; Jafri, Anjum; Giddings, Olivia; Stamler, Jonathan S.; Gaston, Benjamin; Reynolds, James D.; Pediatrics, School of Medicine
    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 (FENO) is associated with asthmatic airway inflammation. We hypothesized that FENO 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 FENO using an inhalational challenge model in normal human subjects. FENO increased in all subjects tested, with a median t1/2 of 32.0 min. Taken together, these data demonstrate that FENO reports, at least in part, GSNO breakdown in the lungs. Unlike GSNO, NO is not present in the lungs in physiologically relevant concentrations. However, FENO following a GSNO challenge could be a non-invasive test for airway GSNO catabolism.
  • Thumbnail Image
    Item
    Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5
    (American Thoracic Society, 2021-07) Raffay, Thomas M.; Bonilla-Fernandez, Koby; Jafri, Anjum; Sopi, Ramadan B.; Smith, Laura A.; Cui, Feifei; O’Reilly, Maureen; Zhang, Rongli; Hodges, Craig A.; MacFarlane, Peter M.; Deutsch, Gail; Martin, Richard J.; Gaston, Benjamin; Pediatrics, School of Medicine
    Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.